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ASH1L LONGITUDINAL CASE PROFILE
Report transcript + cDNA
Report protein consequencep.Arg2146*
Normalized MANE/map notationNM_018489.3:c.6436C>T · NP_060959.2:p.Arg2146*
A warm, determined preschool-age girl with a highly variable history across development, communication, growth, feeding, bowel function, movement, vision, sensory regulation, spells, sleep, temperature, and medication response
Chapter 01Overview and genetics
She is an affectionate, curious, energetic, funny, and determined preschool-age girl. Her family describes her as often joyful. She enjoys active play, coloring, music, making noise at the piano, dancing, water, lights, and playing with other children. When something captures her interest, she can remain focused and deeply engaged.
She is verbal and social. Clinical visits have captured her playing, coloring, communicating, climbing, and engaging warmly with the people around her. She gets up and dresses herself and wants to participate in ordinary family and school life.
Her functioning is also strikingly variable. At some times she is talkative, coordinated, playful, and easy to engage. At others she may become quieter, harder to reach, unusually floppy or stiff, less coordinated, more sensory-sensitive, or temporarily less able to use skills that are available at baseline. Her teacher has also noticed several visibly different functional states. These shifts can occur within one day as well as across days and may coincide with fatigue, bowel difficulty, illness, sensory overload, or other physical strain. Her history is one of fluctuating access to skills rather than established developmental regression, and no single neurological mechanism has been identified.
Her sociability creates a practical safety concern. A clinician once observed appropriate stranger anxiety, but her family says that she sometimes approaches or readily engages unfamiliar adults with limited caution. She may also climb, jump, or move toward danger without appreciating the risk. Close supervision remains important without treating her friendliness, curiosity, or drive for independence as problems in themselves.
Trio whole-exome sequencing identified a heterozygous, de novo, pathogenic nonsense variant in ASH1L: c.6436C>T, p.(Arg2146*). The variant was not detected in either tested parent, and no secondary findings were reported. The family received the molecular diagnosis when she was approximately 27 months old.
The premature stop is predicted to disrupt normal ASH1L function. That is a molecular prediction; no patient-specific RNA, protein, or other functional study has measured the variant’s effect in her cells. The diagnosis provides an important explanation for her neurodevelopmental history, but it does not prove that every gastrointestinal, endocrine, immune, temperature, medication-response, or other feature described below was caused by ASH1L.
The pregnancy was described as healthy, and she was born full term. Her birth weight was 7 pounds 15.9 ounces, approximately the 78th percentile. She passed newborn hearing screening in both ears.
During labor, her family recalls that her heart rate dipped slightly with contractions and that a nurse used the word “arrhythmia” while preparations for a possible cesarean delivery were underway. The tracing normalized, and her family reports that the post-birth cardiology assessment was reassuring. No fetal or neonatal arrhythmia was diagnosed.
Her early oral pattern was unusual. She never accepted a pacifier, and her suck did not look typical to her family. At times, cheek stimulation, bottle repositioning, or repeated prompting was needed to keep her feeding. A feed could require substantial effort while producing relatively little intake. Her family also recalls rolling-like movement at approximately ten days old, although this was an early family observation rather than a formally assessed milestone.
During roughly the first two months, she passed stool about every 48 hours. At approximately two months, while she had a runny nose and brief cough without fever, her family observed blood-tinged spit-up; telephone triage favored a small nasal-source bleed. Large-volume spit-ups then became prominent, sometimes forceful or projectile and sometimes occurring during burping. Her bowel pattern subsequently changed to frequent loose stools, often five to seven times daily and at times described as foul-smelling, greasy, or floating.
Soft foods remained especially important during approximately her first two years. No aspiration or choking disorder was reported, no dysphagia was diagnosed, and no swallow study was completed. Later genetics visits recorded no current feeding or swallowing difficulty.
Chapter 02Development, neurologic events, and sleep
Developmental, expressive and receptive language, motor, behavioral-regulation, and sensory concerns contributed to her evaluation. Her family felt that speech lagged more than gross movement.
At approximately 31 months, a formal neurological examination recorded gestures and one- to three-word sentences with mildly reduced articulation. By approximately 33 months, her family estimated that she used about 200 words, with vocabulary continuing to expand. She could communicate meaningfully, although unfamiliar listeners sometimes had difficulty understanding her.
Her family has not described a major loss of acquired skills. Instead, access fluctuates: speech, coordination, engagement, and regulation may be readily available at one time and much harder to access at another. During later off-baseline periods, she could begin a day quietly, use little speech for several hours, move more rigidly, or become rougher and more dysregulated before returning toward herself.
She plays with other children and has repeatedly been described as affectionate and socially interactive. Her family reports that developmental pediatrics did not identify an autism concern at the time of that evaluation. No formal cognitive score has been reported.
Her family later reported that the new preschool plan would provide an early-childhood teacher on each day she attended. Earlier school material described weekly early-childhood support and approximately monthly occupational, physical, and speech-language therapy, so the implemented frequency may have changed during the school year. Across settings, goals included initiating and responding with words, joint attention, reciprocal play with prompting, communication, motor planning, sensory regulation, safety awareness, and recognizing when a behavior change may signal physical discomfort.
Later school reports documented continued gains: she used one- to two-word phrases with models, navigated the school environment well, and showed good motor planning during playground activity. She improved to alternating feet on stairs, while skipping or galloping remained asymmetric, with the right foot leading. Observations varied by discipline and setting; reassuring school function does not mean that home or episodic motor concerns were absent.
She remains verbal, social, and independently mobile, although gait and access to speech continue to fluctuate. She can dress herself and eats without a current swallowing-safety concern. Her bowel course and treatment are summarized below.
Her family observed tremor-like shaking from infancy. The early pattern consisted of daily, low-amplitude, rapid shaking of both arms, often most noticeable on waking, with the elbows and fingers flexed. Her walking was not interrupted by these events. Horizontal “no-no” head movements occurred approximately once or twice per week, sometimes after frustration or a loud sound, with rapid return to baseline.
One video appeared to the family to show head movement during sleep, but the reviewing neurologist thought she was awake with her eyes closed. The clinician considered the early tremor and head-shaking pattern reassuring and not typical of seizures. Her family reports that a prior approximately 30-minute EEG was normal.
Because the events were frequent and seizures can occur in people with ASH1L-related disorders, a four-hour video EEG was completed at approximately 31 months. It showed:
The family believed she appeared to sleep for approximately two hours, but the EEG did not document stage II sleep. That single recording was not a polysomnogram and does not show that she fails to reach stage II sleep in ordinary life. The mild slowing was abnormal but nonspecific. It does not establish epilepsy, a particular cause of brain dysfunction, or a chronic sleep-stage disorder.
The family provided a report summary of a later ambulatory video EEG lasting 43 hours 31 minutes that captured N1, N2, N3, and REM sleep. In that summary, no seizures or interictal epileptiform activity were identified. Two possible blank-stare events had no electrographic seizure correlate, and the ECG channel showed no significant change. A subsequent sleep-clinic note summarized the posterior background as 4–5 Hz, compared with 6–7 Hz on the earlier study. The slower background description remains nonspecific. She has no confirmed epilepsy diagnosis and has not been treated with an antiseizure medication.
The family also describes brief episodes that differ from the early tremor. During these, she may become still or appear to freeze for approximately 30 seconds to two minutes, sometimes covering her ears or eyes, closing her eyes, rocking, or remaining partly responsive. She may look frightened or briefly confused but generally returns quickly to baseline.
During one episode at approximately 35 months, she sat in a corner with her eyes closed, covered her ears, and rocked. She remained purposeful and verbal enough to ask to be left alone, illustrating that at least some of these episodes include partial responsiveness.
At other times, her family has observed fixed staring with her head held to one side. This has not been formally classified and cannot be assumed to be the same event as either the sensory shutdowns or the pain-associated breath and limp episodes.
These episodes have not been captured with a confirmed electrographic seizure. Partial responsiveness and an association with sound or overwhelm have sometimes suggested a sensory shutdown to the family, but no clinical evaluation has assigned them a definitive sensory, seizure, cardiac, or autonomic classification.
Beginning at approximately 33 months, her family observed a separate group of events involving an inability or delay in initiating a cry or breath, altered color, limpness, stiffness, eye movement, sweating, or altered awareness. By the later sleep evaluation, family tracking and the clinic history described approximately eleven events in this broad category, although not every event was medically witnessed or described in equal detail.
The better-characterized sequence includes:
At the later sleep evaluation, the caregiver described pauses in breathing with stiffening or body contortion and fatigue afterward. This was reported history rather than an event observed during the visit.
Some events followed pain or crying, while others occurred during periods of gastrointestinal difficulty, waking, or temperature change. Recovery was usually rapid, although sleep sometimes followed. Clinically, the events remain unclassified. Features overlap with breath-holding, syncope, reflex-anoxic events, seizure-like activity, and cardiac or autonomic phenomena, but none of those explanations has been confirmed.
During the first hand-foot-and-mouth illness period, the family also observed a temporary one-sided mouth droop. It improved, and a later formal neurological examination found symmetric facial movement.
Her family reported a bedtime near 8:30 p.m., although she could remain awake until approximately 11:30 p.m. Once asleep, she usually slept through the night and woke near 7 a.m. She did not routinely nap on preschool days but sometimes fell asleep on the couch at home. Naps could improve regulation, while late-evening bursts of energy also occurred.
She occasionally sleeps with her mouth open. Her family has also observed brief soft cries from sleep lasting approximately 30–60 seconds, with little initial response to voice or touch followed by spontaneous self-soothing. After some waking periods, they have noticed head touching, shivering, cold complaints, unusual eye behavior, or a slow return to full engagement.
Sweating during naps has been recurrent, including one episode in which one side of her body was described as soaked. No polysomnogram has been completed, and no sleep disorder has been diagnosed.
At a later sleep-medicine visit, the family described sleep-onset latency of up to about three hours, restless light sleep with frequent movement and marked night sweating, and a tendency to end the night in a parent’s bed. When not awakened early, she often slept from roughly 11 p.m. to 9 a.m. Naps were uncommon, excessive daytime sleepiness was not reported, and intermittent mouth breathing or snoring was not loud or nightly; no witnessed apneas were reported.
The clinician assessed delayed sleep onset, restlessness, and reduced total sleep, considering neurodevelopmental and gastrointestinal contributors as well as possible iron deficiency. A later bedtime with less time in bed and a reward-based plan for remaining out of the parents’ room were discussed. The family later reported follow-up values of serum iron 139 µg/dL and ferritin 17 ng/mL. These reported values do not by themselves establish the cause of her sleep difficulty.
On examination at that visit, the nares were patent, tonsils small, heart rhythm regular without a murmur, lungs clear, abdomen soft and nontender, and tone, strength, coordination, reflexes, and gait documented as normal. This was a reassuring snapshot during one visit and does not erase the longitudinal variability described elsewhere.
Chapter 03Feeding, gastrointestinal history, and ENT/imaging
In addition to the early suck and dependence on soft food, her family has described a high-arched palate, intermittent raspy voice, occasional mouth-open sleep, and difficulty grading a spoon accurately toward her mouth. Later chewing or picking at nails, toes, skin, and surrounding tissue has sometimes been intense; on one occasion she removed a toenail.
Later genetics reviews recorded no dental concern and no current feeding or swallowing problem, and her family does not recall notably delayed tooth eruption. No formal chewing disorder has been diagnosed.
Appetite and fullness signals can be difficult to interpret. At times her appetite improves after a bowel movement. At other times she refuses food in a way that appears sensory. Her appetite varies rather than showing consistent excessive hunger.
Her bowel history has changed markedly over time.
During the first two months, she stooled approximately every 48 hours. After the early illness and onset of large-volume spit-ups, she developed a long period of frequent loose stool—often five to seven times per day and sometimes described as greasy, floating, or strong smelling. Reflux-like large spit-ups, occasionally forceful or projectile, were also prominent in infancy.
Later testing was reassuring against several common explanations for chronic loose stool:
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| Test | Result | Clinical interpretation |
|---|---|---|
| Fecal elastase | >800 μg/g | Did not support pancreatic insufficiency |
| Fecal calprotectin | 22 μg/g | Did not show marked intestinal inflammation |
| 72-hour fecal fat | 0.4 g/24 hours | Did not support significant fat malabsorption |
| Bile acids | 3.5 μmol/L | Reported within the expected range |
PT/INR and vitamins A, D, and E were reported as normal, as was celiac screening. These results do not identify the cause of the earlier loose-stool pattern or the infant spit-ups.
At approximately 30 months, she developed the first of three illnesses identified as hand-foot-and-mouth disease. The first illness included fever and her first known acetaminophen exposure. Within the first hour, her family observed a perioral rash, eyelid puffiness, and an abrupt change in which she remained awake but appeared unusually disengaged or shut down. The acute change resolved. Acetaminophen is now listed in her clinical record because of rash.
During the same broader illness and medication window, her bowel pattern shifted dramatically from frequent loose stools to constipation. The family also observed the temporary facial asymmetry described above. The timing is important, but it does not prove that acetaminophen caused the altered state, facial change, or lasting bowel transition.
Two additional illnesses identified as hand-foot-and-mouth disease occurred at approximately 32 months and again just before 33 completed months. They were not accompanied by fever or acetaminophen exposure, cleared relatively quickly, and were followed by continued or worsening constipation. Her family reports that she has not had another fever since the first hand-foot-and-mouth illness described above, including during the two later hand-foot-and-mouth illnesses. This observed history does not show that she is unable to mount a fever.
By approximately 34 months, constipation required daily medication. Treatment began with approximately 10.5 mL of lactulose daily, later increasing to 12 mL, with 3.75 mg of senna added. Polyethylene glycol had provided limited benefit during an earlier stage. Even with treatment, her family documented days with no bowel movement, smear-only output, large hard Bristol type 1 stools, mucus or liquid passing around retained hard stool, alternating stool forms, and episodes of pain or vomiting. A bright-red posterior fissure and perianal swelling were observed.
At approximately 35 months, she was already taking daily lactulose and senna when the severity of her retention became unmistakable. A stool log had appeared encouraging only two days earlier, and she showed no obvious abdominal pain. An emergency examination found her active and well appearing, with a soft, nontender abdomen. Imaging nevertheless showed a large amount of stool throughout the colon and rectum, including a large rectal stool ball; her family recalls being told that the retained stool amounted to approximately two feet. A glycerin suppository produced only hard fragments, and follow-up imaging still showed moderate-to-large stool burden. For her, visible comfort, a reassuring abdominal examination, daily medication, and apparently encouraging stool output did not reliably mean that her bowel was empty.
A clinician then directed a two-part polyethylene-glycol cleanout. The first part used 2.5 capfuls in 16 ounces; she drank approximately 12 ounces and passed a large, predominantly liquid output. The second used 1.5 capfuls in 10 ounces, which she completed, followed by formed and then loose stool. The maintenance regimen was adjusted repeatedly. By approximately 36 months, it had reached lactulose 15 mL twice daily and senna 15 mg twice daily, with clinician-directed rescue using glycerin suppositories or saline enemas. These doses describe her historical medical course; they are not treatment advice.
The evening immediately before anorectal manometry and Sitz-marker ingestion, a 33 mL saline enema produced a bowel movement within approximately five minutes. The next day, anorectal manometry and the first portion of the Sitz-marker study were completed. Both studies therefore occurred after rectal rescue treatment and while she remained on an active daily bowel regimen, rather than at an untreated baseline. Reported manometry values included an anal-sphincter length of 3.5 cm, resting pressure of 65 mm Hg, a present rectoanal inhibitory reflex, squeeze pressure of 189 mm Hg, and no spasms or prolonged return to baseline. The intact reflex, resting pressure, and strong squeeze were reassuring. Because of her age, however, defecation dynamics and rectal sensation were not assessed; the study therefore did not evaluate every possible contributor to incomplete evacuation.
For the Sitz-marker study, she swallowed approximately 22–23 of 24 markers, and the first radiograph was obtained that day. Two markers reportedly remained on a later film, and a third film was obtained several days later. The low remaining marker count reflected transit during that particular testing period, but it did not explain why she continued to experience severe intermittent retention in daily life. No specific outlet or motility diagnosis was assigned.
The family also tried two informal blue-dye observations. During one period, a clear color change was not seen for approximately nine days; after a later increase in the bowel regimen, green stool appeared at approximately 35 hours. These were home observations, not standardized transit tests.
Through the following months, the prescribed regimen reached lactulose 15 mL twice daily and senna 15 mg twice daily, although later entries show that she did not consistently accept every dose. Recurrent retention included smear-only output and repeated 33 mL saline-enema rescue with Bristol type 1 stool in late winter and spring. One episode followed a suppository that produced only a small stool. Daily stooling still did not reliably indicate complete evacuation.
In early spring, the family log shows a change from a 15 mg senna chew to liquid senna; the liquid concentration, volume, and equivalent dose were not documented. During the ambulatory EEG, two days of accepting only sips or partial doses coincided with no true bowel movement and then smear-only output. After the leads were removed and medication was accepted, she passed a large stool. This chronology is important but does not prove that either the EEG setup or medication acceptance caused the stool change.
By later spring and summer, medication acceptance was a major part of the bowel course. Most morning entries through late summer marked lactulose and liquid senna as not taken or refused, with occasional missed evening doses. She continued to stool on many days but had recurrent stool-free and smear-only days. After mid-spring, the family log contains no further enema or suppository entry; this means none was recorded, not that none occurred. The later interval therefore reflects both persistent bowel variability and substantial medication-acceptance limitations, not documented failure of a consistently administered twice-daily regimen.
During one prolonged off-baseline period, family notes recorded rigid movement, marked dysregulation, and several hours with little speech alongside medication refusal, smear-only or absent stool, and later suppository or enema rescue. The co-occurrence does not establish that retention caused the functional change.
She has also vomited during car travel and, at times, shown very little outward distress afterward. This fits her broader pattern of inconsistent outward responses to pain and internal discomfort. No cyclic-vomiting, vestibular, or autonomic diagnosis has been made.
The dose strip includes every consecutive dated medication entry in this audited interval. Weight is shown only on the seven dates when the log records it. Stool descriptions, smears, suppositories, and Bristol types remain in the complete profile narrative; they are not converted into a severity score. The parallel timing does not establish causation.
Lactulose, mL Senna, mg
At approximately 29 months, brain MRI with and without contrast was normal intracranially for age. Midline structures, cerebral volume, myelination, morphology, pituitary appearance, and gray- and white-matter signal were age appropriate. There was no mass, hemorrhage, infarction, hydrocephalus, migration abnormality, abnormal enhancement, or other structural brain explanation for her developmental or movement history.
The MRI did show near-complete bilateral paranasal sinus mucosal thickening and opacification and a trace, likely postinflammatory left mastoid effusion. Her family did not recall obvious congestion, fever, ear pain, or drainage at the time. Neurology explained that these can be incidental findings in young children, are not fluid on or around the brain, and were not shown to be specifically related to ASH1L.
The post-contrast portion was limited to an axial T1 sequence despite repeated attempts to re-sedate her. The documented medication sequence included intranasal midazolam 2 mg, intranasal dexmedetomidine 42 micrograms, and two intravenous midazolam doses of 0.5 mg each. Sedation remained unexpectedly inadequate. A diagnostic MRI report was issued despite the limited post-contrast portion, and no acute procedural complication was recorded. Her family reports that she remained awake or active until late that evening and that future sedated procedures were flagged for planning under general anesthesia.
Dexmedetomidine is listed in her clinical record as having the “opposite effect.” This was one unusually difficult sedation episode. It does not prove a generalized medication resistance, an allergy to anesthesia, a receptor-level mechanism, or an ASH1L-wide sedation pattern.
Formal audiology several days after the MRI found:
Some tone responses may have been above true threshold because her conditioned response slowed, and headphones were not attempted. The test was not ear-specific pure-tone audiometry, but hearing was considered adequate for speech and language access. Monitoring was advised. No recurrent ear-infection history was reported at that time.
At approximately 35 months, an emergency clinician described the left eardrum as red but did not diagnose acute otitis media or prescribe antibiotics. The family later reported a clear ENT examination. At other times, they have observed clear drainage from the left nostril, ear pressing, apparent nose discomfort on waking, occasional mouth-open sleep, intermittently “wet”-sounding breathing, and a raspy voice. No chronic ear, sinus, airway, or voice diagnosis has been established.
Chapter 04Movement, vision, and sensory regulation
Low tone and hypermobility appear in her clinical history, while her family describes tone as state dependent. At times she can appear strong, highly active, and coordinated. At others she may seem rag-doll-like or floppy, unusually stiff, or less able to coordinate her body.
Family and therapy observations have included a wide, galloping, unsteady, or asymmetric gait; frequent falls; occasional limping or leg dragging; temporary body tilting or leaning; weak or delayed postural corrections; difficulty grading movement; overshooting or undershooting a spoon; and running into objects. During one period at approximately 35 months, she was unable to carry a preschool backpack weighing no more than about three pounds and fell backward repeatedly.
Her family identifies the left leg as longer. The degree of the difference and its effect on her pelvis, posture, or gait have not yet been formally measured.
At approximately 35–36 months, a gait change lasting several days included the left leg appearing to give out, stiffen, or drag during climbing. It improved after an increase in senna and greater stool output. That temporal improvement does not prove that stool retention caused the gait change.
These longitudinal concerns coexist with a reassuring formal neurological examination at approximately 31 months: tone, bulk, strength, reflexes, sensation, fine-motor function, gait, and balance were normal that day; no abnormal movement or reaching ataxia was seen; and she climbed and changed position independently. The contrast is important. Her difficulties fluctuate, and a normal examination at one visit neither invalidates family observations nor predicts every other state.
Later school records noted improved stair use with alternating feet, while skipping or galloping remained asymmetric, with the right foot leading. At the later sleep-medicine visit, another formal examination documented normal tone, strength, coordination, reflexes, and gait on that day. Her family continues to identify the left leg as longer, but an objective measurement and its effect on pelvic alignment or gait have not been documented.
Her visual history includes bilateral hyperopia, astigmatism, intermittent or frequent esotropia, and glasses. Esotropia was directly observed at more than one clinical visit. An earlier prescription was approximately +4.50 sphere/+1.00 cylinder in the right eye and +4.00 sphere/+0.50 cylinder in the left, followed later by approximately +3.50/−0.50 in the right and +2.50/−0.50 in the left. Because the prescriptions use different cylinder notation, the numerical change cannot be interpreted as a simple improvement or worsening.
Pediatric ophthalmology later documented alternating intermittent esotropia and bilateral hyperopia. The esotropia was described as historically present from birth and small or intermittent during that examination. Glasses versus observation were discussed; a small or intermittent finding on one examination does not erase the more frequent eye turning observed at other times.
School physical-therapy observations added a functional view. Without glasses, she often held her gaze straight ahead or downward and appeared reluctant to look up. Alternating convergence increased with upgaze, and the left eye moved inward during repeated upgaze. Her eye position and visual access showed definite improvement with glasses, although she needed encouragement to keep them on.
In a later ophthalmology visit described by the family, visual acuity was not the clinician’s main concern; the focus remained both eyes turning. Drops were prescribed for use as needed to blur vision and support glasses wear. The clinician was not concerned by her limited upgaze at that visit, and follow-up was planned. These findings support continued monitoring rather than showing that the earlier esotropia had resolved.
Thunder, airplanes, garage doors, and other loud or unexpected sounds may lead to shaking, freezing, covering her eyes or ears, shutting down, or saying that she is scared. Hugs, clear structure, and deep pressure can help her recover. At other times, she actively seeks music, noise, movement, inversion, water, and intense sensory input. These are not contradictory; her response depends on context and body state.
During some periods of internal distress, her family has observed upside-down positioning, pinching at her face or chest, pressing herself into corners or boundaries, nail or skin picking, and more difficulty settling. Head banging had stopped by the later genetics visit, but fist slamming, pinching, and picking or chewing at nails, toes, and skin continued intermittently.
Her outward pain response is reduced, delayed, inconsistent, or sometimes mislocalized—not absent. At times she can run into a wall or take another hard impact with almost no visible reaction; at other times, a similar or smaller event can produce intense distress or a full meltdown. She may show little reaction after vomiting on one occasion yet respond clearly to an injection or another injury. After one bite to her back, she said that her arm hurt and indicated the arm. The same mismatch appeared during severe constipation: she showed no obvious abdominal pain and had a soft, nontender abdomen despite extensive retained stool and a large rectal stool ball. This does not mean that she feels no pain. It means that the intensity, location, and timing of her outward response may not reliably show what her body is experiencing. Adults may therefore need to look for indirect changes in behavior, movement, appetite, sleep, or regulation rather than assuming that a quiet reaction means she is comfortable.
Her family distinguishes ordinary preschool frustration from longer off-baseline changes affecting several domains together: speech access, coordination, muscle tone, sensory response, roughness or aggression, sleep, pain behavior, and ability to engage. Because several functional domains change together, these periods extend beyond ordinary preschool frustration.
During one such off-baseline stretch, she repeatedly used the phrase “control body.” Her family recorded the words without assuming exactly what she was trying to communicate, but they were notable in the context of visible changes in movement and regulation.
Chapter 05Growth, immune, autonomic, and treatment history
Slow growth and poor weight gain have been persistent concerns. Selected health-system measurements show the overall decline and a later abrupt rise and reversal:
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| Approximate age | Weight or measurement | Recorded percentile |
|---|---|---|
| Birth | 7 lb 15.9 oz | ~78th |
| 26 months | 21.2 lb | Below 1st |
| 29 months | 23 lb 2.4 oz | ~2nd |
| 31 months | 27 lb 8.9 oz | ~32nd |
| 33 months | 23 lb | 0.67th |
| 33 months | Height 86.5 cm; head circumference 45.7 cm | 4.7th; 4.17th |
All of the cited weights—including the abrupt rise and subsequent fall—were obtained on clinic scales. Her family observed visible, rapid changes in her body or tissue appearance during this period and believes the pattern reflected a genuine physiological change rather than ordinary growth alone. The cause remains unresolved; hydration, stool burden, measurement conditions, tissue or fluid change, or another factor may have contributed. A formal examination at the 31-month visit did not document peripheral edema.
These five milestones are selected from the available weight record; they do not replace a clinical growth chart or the complete weight history. Source labels and reported percentiles are preserved. Decimal pounds are used only to size the bars; the printed weight remains the reported value.
about 78th percentile
below 1st percentile
about 2nd percentile
about 32nd percentile
0.67th percentile
Reported endocrine testing included:
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| Test | Result | Reference range or note |
|---|---|---|
| IGF-1 | 17 ng/mL | Reference 86–323; reported Z score below −3 |
| Repeat IGF-1 | 34 ng/mL | Reference 37–272 |
| Later IGF-1 | 36 ng/mL | Reported in a genetics history |
| IGFBP-3 | Within range | — |
| ACTH | 92.6 pg/mL | Reference 7.2–63.0 |
| Cortisol | 10.1 μg/dL | Reported within range |
| Thyroid testing | Reported within range | — |
The brain MRI described a normal pituitary. Endocrine follow-up has continued, but these findings have not established growth-hormone deficiency, adrenal insufficiency, thyroid disease, pituitary disease, or another primary endocrine diagnosis.
Testing documented several abnormalities across blood counts, chemistry, complement, lymphocyte counts, cytokines, and antibody responses. No unifying immune diagnosis has been assigned.
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| Approximate age | Finding | Result | Laboratory reference |
|---|---|---|---|
| 29 months | Platelets | 603 ×10³/μL | 150–450 |
| 29 months | Albumin | 5.1 g/dL | 3.8–4.7 |
| 29 months | Total protein | 7.3 g/dL | 5.9–7.2 |
| 29 months | Total bilirubin | 0.6 mg/dL | 0.1–0.4 |
| 36 months | Red blood cells | 5.18 ×10⁶/μL | 3.94–4.97 |
| 36 months | Hemoglobin | 14.5 g/dL | 9.9–13.4 |
| 36 months | Hematocrit | 42.2% | 30.0–40.0 |
| 36 months | Platelets | 538 ×10³/μL | 212–480 |
The 29-month specimen was reported as moderately hemolyzed. The later erythrocyte, hemoglobin, hematocrit, and platelet values were mildly high. Inflammatory markers were not elevated in the reported testing: ESR was 4 mm/hour, and CRP was within range.
Complement testing showed C3 159 mg/dL against a range of 80–150, while C4 was within range. Lymphocyte-subset testing at approximately 36 months showed:
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| Cell population | Percentage | Absolute count | Laboratory reference |
|---|---|---|---|
| CD3 T cells | 58% | 3,016 cells/μL | 43–77%; 918–4,610 cells/μL |
| CD4 T cells | 40% | 2,080 cells/μL | 26–53%; 529–2,585 cells/μL |
| CD8 T cells | 16% | 832 cells/μL | 13–32%; 278–1,553 cells/μL |
| CD19 B cells | 21% | 1,092 cells/μL | 13–34%; 390–1,009 cells/μL |
| CD16/56 natural-killer cells | 21% | 1,092 cells/μL | 6–22%; 120–721 cells/μL |
The CD4 ratio was 2.5, within the displayed range of 0.8–4.1. T-cell values were within range. The B-cell and natural-killer-cell percentages were also within range, while both absolute counts were high. The formal report recorded the same absolute value—1,092 cells/μL—for the B-cell and natural-killer-cell populations.
At approximately 36 months, total IgG, IgA, IgM, IgE, IgG subclasses, and T-cell ratios were reported within their laboratory ranges. Repeat testing at approximately 42 months showed:
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| Test | Result | Laboratory reference |
|---|---|---|
| Total IgG | 579 mg/dL | 451–1,071 |
| IgG1 | 359 mg/dL | 281–755 |
| IgG2 | 73 mg/dL | 54–271 |
| IgG3 | 30 mg/dL | 16–84 |
| IgG4 | 7 mg/dL | 1–71 |
| Tetanus antitoxoid IgG | 0.48 IU/mL | Laboratory response threshold ≥0.10 |
| Diphtheria antitoxoid IgG | 0.49 IU/mL | Laboratory response threshold ≥0.10 |
All of these values met their displayed laboratory ranges or response thresholds.
A 23-serotype pneumococcal antibody panel at approximately 40 months showed:
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| Serotype | Result (μg/mL) | Serotype | Result (μg/mL) |
|---|---|---|---|
| 1 | 0.3 | 22F | 1.4 |
| 2 | <0.1 | 23F | 1.1 |
| 3 | 0.2 | 6B | 0.6 |
| 4 | 0.2 | 10A | 1.1 |
| 5 | 0.1 | 11A | 0.4 |
| 8 | 0.5 | 7F | 0.3 |
| 9N | 0.2 | 15B | 1.5 |
| 12F | 0.2 | 18C | 0.1 |
| 14 | 0.2 | 19A | 0.8 |
| 17F | 0.4 | 9V | 0.2 |
| 19F | 1.3 | 33F | 1.8 |
| 20 | 0.8 | — | — |
Six of 23 serotypes—19F, 22F, 23F, 10A, 15B, and 33F—were at or above 1.0 μg/mL. The laboratory report stated that, for a single pre- or post-immunization sample in a child younger than six, a response to more than 50% of serotypes at or above 1.0 μg/mL is considered normal. Because this was a single sample rather than a documented paired pre- and post-vaccine challenge, it cannot distinguish a limited initial response from waning antibody levels or determine clinical protection by itself.
A 13-analyte cytokine panel at approximately 40 months showed:
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| Analyte | Result | Laboratory reference |
|---|---|---|
| Tumor necrosis factor alpha | 1.9 pg/mL | ≤7.2 |
| Interleukin-2 | <2.1 pg/mL | ≤2.1 |
| Soluble interleukin-2 receptor (sIL-2R, soluble CD25) | 1,107.0 pg/mL | 175.3–858.2 |
| Interleukin-12 | <1.9 pg/mL | ≤1.9 |
| Interferon gamma | <4.2 pg/mL | ≤4.2 |
| Interleukin-4 | <2.2 pg/mL | ≤2.2 |
| Interleukin-5 | <2.1 pg/mL | ≤2.1 |
| Interleukin-10 | 6.0 pg/mL | ≤2.8 |
| Interleukin-13 | <1.7 pg/mL | ≤2.3 |
| Interleukin-17 | <1.4 pg/mL | ≤1.4 |
| Interleukin-1 beta | <6.5 pg/mL | ≤6.7 |
| Interleukin-6 | <2.0 pg/mL | ≤2.0 |
| Interleukin-8 | 3.1 pg/mL | ≤3.0 |
Three of the 13 analytes were above their displayed ranges: soluble IL-2 receptor, IL-10, and, minimally, IL-8. Interleukin-2 itself was not elevated; IL-2 and soluble IL-2 receptor are different measurements.
Taken together, these tests document thrombocytosis on two occasions, mildly high red-cell measures, high absolute B-cell and natural-killer-cell counts with percentages within range, mildly high C3, selective cytokine elevations, and six of 23 pneumococcal serotypes at or above the laboratory’s 1.0 μg/mL threshold in a single sample. They do not, by themselves, establish immune deficiency, immune dysregulation, a cytokine disorder, chronic inflammation, or an ASH1L-specific immune mechanism.
The two source tables display different laboratory intervals, so each result remains paired with the interval printed beside it. The shared plotting domain supports visual comparison without replacing either source reference.
603 ×10³/μLAbove displayed range
538 ×10³/μLAbove displayed range
Her notable infectious history during this period consisted of the three illnesses identified as hand-foot-and-mouth disease described above. There was no established pattern of recurrent pneumonia, antibiotic-treated ear infection, deep bacterial infection, or other unusual bacterial disease.
Her skin is described as sensitive, with recurrent diaper rash, occasional unexplained rashes, slow hair growth, feet that may become red or sweaty, and picked or chewed areas that can remain irritated. The rash and eyelid puffiness after the first acetaminophen exposure are part of the medication chronology. No unifying dermatologic, mucosal, allergic, or immunologic diagnosis has been established.
Her family reports that she has had no fever since the first hand-foot-and-mouth illness in this history. They also repeatedly observe cold or mottled hands and feet, red or sweaty feet, pronounced cold sensitivity compared with peers, and heavy sweating during sleep or some spells. During some awake off-baseline periods, they have observed pallor or mottling elsewhere on her skin. At preschool she may remain cold despite extra layers. During some off-baseline periods she has asked for a cold bath or sought unusual body positions.
At approximately 35 months, repeated home temporal readings on the same device and site moved from 96.9°F to 96.7°F to 94.8°F, while other household members read in the 98°F range. Her temperature later returned to the 98°F range without active warming. During another sleep-related sequence, the device first read “Lo,” followed by 93.2°F, 94°F, and 96°F; her trunk was sweaty while her forehead felt cool, and there was no reported respiratory distress. At approximately 38 months, one nap produced one-sided soaking sweat.
These readings and physical observations are important to her family’s recognition of off-baseline states. They were obtained at home and do not establish clinically verified hypothermia, dysautonomia, abnormal thermogenesis, or one specific autonomic mechanism.
At the later sleep evaluation, the family reported low home readings during roughly three quarters of evening checks, often near 95°F and rising to about 96°F within 30 minutes, while she did not feel cold to touch. The clinician discussed possible dysautonomia as one consideration in the context of her genetic diagnosis. This was a discussion point, not a diagnosis, and no formal autonomic evaluation is documented.
The labor-monitor concern is described above. The later four-hour EEG formally labeled its regular single-channel ECG tracing as tachycardia at 100–200 beats per minute, but an EEG channel cannot diagnose or exclude an arrhythmia. A subsequent family-provided cardiology summary describes a 12-lead ECG with sinus rhythm, PR 80 ms, QRS 60 ms, and QTc 409 ms, with artifact noted. An echocardiogram was technically limited but did not identify structural heart disease; a patent foramen ovale was not excluded, and several right-sided pressure, coronary, pulmonary venous, and aortic-arch views were incomplete.
The family later reported that the cardiology follow-up remained reassuring, but none of her typical loss-of-awareness events was captured during the cardiac testing described. A 30-day ambulatory monitor was planned after summer. A completed monitor result has not been reported.
At approximately 35 months, strong-smelling urine prompted catheterized urinalysis during an emergency evaluation; the family reports that it was negative. At approximately 38 months, the family recorded one interval of about 14 hours without urination during the broader bowel and temperature course. No recurrent urinary pattern, urinary-tract infection, kidney disease, or bladder diagnosis has been established.
Family records also show a repeated blood-draw laterality pattern: during one spring draw, a left-arm attempt was unsuccessful and the right arm succeeded; in a later interval, two left-arm attempts were unsuccessful and a right-arm draw succeeded on the first attempt several days later. These are parent-recorded procedural observations. They do not establish a vascular disorder, obstruction, or ASH1L-related mechanism.
The principal medication-response observations are:
Her history includes a de novo pathogenic ASH1L variant; developmental and language differences; slow and irregular growth; early oral and feeding differences; a profound bowel shift with later medication-acceptance limits; fluctuating tone and coordination; vision needs; sensory shutdowns; tremor and later breath, limp, or stiff events; two prolonged EEG evaluations without captured electrographic seizures; difficult MRI sedation; sleep-onset and restless-sleep concerns; unexplained laboratory findings; and family-observed changes in temperature, sweating, pain response, vascular access, and overall state.
Those findings are real parts of her life, but they are not the whole of it.
She is affectionate, social, funny, musical, active, curious, and determined. She communicates, colors, dresses herself, plays with other children, seeks connection, and continues to gain skills. A difficult hour or day is not her permanent baseline, and a reassuring clinic examination does not erase what happens at other times.
Her ASH1L diagnosis is an important molecular anchor. It does not prove that one immune, autonomic, endocrine, gastrointestinal, sleep, or medication-response mechanism explains everything. Understanding her requires holding her abilities and relationships together with the substantial, fluctuating work her body must do across communication, movement, feeding, bowel function, sleep, sensory regulation, temperature, growth, and everyday safety.
Displayed scale: 23–24 lb