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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 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.