Table 1.
Phenotypes of Patients With MAGEL2 and L1CAM Mutations
| Patient/Sex (M/F) | Patient 1 | Patient 2 | Patient 3 | Patient 4 | Patient 5 |
|---|---|---|---|---|---|
| F | F | F | M | M | |
| Ethnicity | White European | White European | White European | White Chilean | Afro-Caribbean |
| Mutation | c.1996dup, p.Q666Pfs*47 | c.1996dup, p.Q666Pfs*47 | c.1996dup, p.Q666Pfs*47 | c.1996dupC, p.Q666Pfs*47 | Hemizygous |
| MAGEL2, NM_019066 | MAGEL2, NM_019066 | MAGEL2, NM_019066 | MAGEL2, NM_019066 | c.1354G>A, p.G452R | |
| De novo | Not maternally inherited; paternal DNA was unavailable | Not maternally inherited; paternal DNA was unavailable | De novo | L1CAM, NM_000425 | |
| Chromosome microarray showed a 16q11 duplication, 45,186,600–45,416670); Nimblegen 135K Hg18 WG CGH v3.1. | Chromosome microarray: normal | Chromosome microarray: normal | Mother is a heterozygous carrier | ||
| Family history | Healthy younger siblings | Healthy older sister | Healthy older sister | Healthy older brother | |
| 2× miscarriages at 7/40 | 2× miscarriages at 7/40 | Mother had bilateral metatarsus varus and a history of recurrent shoulder dislocations | |||
| Prev. stillbirth at 37/40 | Prev. stillbirth at 37/40 | ||||
| Perinatal history | Normal antenatal scans | Polyhydramnios | IUGR and polyhydramnios | — | Antenatal ventriculomegaly |
| Cesarean; breech | DCDA twin pregnancy | DCDA twin pregnancy | Elective LSCS | ||
| Hypotonic and respiratory distress after birth needing oxygen | Cesarean; breech | Cesarean; breech | Born in good condition | ||
| Resuscitation at birth: APGARs – 2 at 1 min; 1 at 5 min |
|||||
| Cooled for HIE | |||||
| Ventilated to day 4 of life | |||||
| Gestation, wk | 40 | 36 + 1/40 | 36 + 1/40 | 38 | 40 |
| Birth weight, kg (SDS) | NA | 2.7 (+0.14) | 2.0 (−1.67) | 3.5 (0.07) | 3.6 (+0.07) |
| Endocrine referral | Short stature and previous history of hypoglycemia | Short stature, diabetes insipidus | Short stature, diabetes insipidus | Growth evaluation, short stature | Hypoglycemic seizures |
| Age at referral, y | 3.2 | 1.10 | 1.10 | 2.8 | 0.7 |
| Height, SDS | −2.14 | −1.3 | −2.0 | −2.84 | −1.7 |
| BMI, SDS | 0.61 | +1.52 | −1.52 | −0.92 | −4.21 |
| Current age, y | 9.7 | 7.6 | 7.6 | 4.7 | 5.0 |
| Height, cm (SDS) | 114.8 (−3.21) | 120.1 (−0.58) | 120.8 (−0.45) | 99 (−1.8) | 99.3 (−1.95) |
| Weight, kg (SDS) | 23.5 (−1.76) | 20.55 (−1.3) | 21.15 (−1.1) | 12.2 (−3.53) | 12.8 (−3.55) |
| Dysmorphic facial features | Long face | Macrocephaly | Macrocephaly | Long face | Bilateral radial clubbed hands |
| Prominent forehead | Long face | Long face | Bitemporal narrowing | Plagiocephaly | |
| Micrognathia | Bitemporal narrowing | Bitemporal narrowing | Prominent forehead | ||
| Prominent forehead | Prominent forehead | Micrognathia | |||
| Hypotelorism | Hypotelorism | Glossoptosis | |||
| Scaphocephalic shape | Scaphocephalic shape | High arched palate | |||
| Micrognathia | Micrognathia | ||||
| Cleft palate | High arched palate | ||||
| Gastrointestinal | GERD | Constipation | Constipation | Gastrostomy for feeding difficulty, gastro-esophageal reflux; chronic constipation | PEG fed |
| Food allergy | Unsafe swallow | ||||
| Dysphagia | |||||
| Constipation | |||||
| Cardiac | No known cardiac pathology | No known cardiac pathology | No known cardiac pathology | Ostium secundum interauricular communication, spontaneous closure | Small VSD |
| Neurodevelopment | Global developmental delay | Severe global developmental delay | Global developmental delay | Global developmental delay | Global developmental delay |
| Bulbar palsy | Gross Motor Function Classification System Level 4 | Independently walking | Autism spectrum disorder | Generalized hypotonia | |
| Wheelchair dependent, nonverbal | Communicates using Makaton, eye gaze, and pointing | Hypotonia | |||
| Able to sit if put in sitting position; attempts rolling over | Some vocalization | Some vocalization | |||
| Some self-harm behavior: head banging | Walking with help | ||||
| Able to sit independently | |||||
| Skeletal system | Arthrogryposis | Distal arthrogryposis | Distal arthrogryposis | Contractures with limited extension of the elbows, knees, hips, and finger | Arthrogryposis |
| Scoliosis | Scoliosis | Hands/fingers tapering | Camptodactyly | Bilateral radial clubbed hands | |
| Flexion deformity of knees | Overlapping fifth finger, positions fingers 3/4/5 together | Small hands and feet | Right hip subluxation | ||
| Short long bones | Scoliosis | ||||
| 11 ribs | |||||
| Ophthalmology | Squint | Optic nerve hypoplasia and severe sight impairment | Mild optic nerve hypoplasia (fundoscopy) and sight impaired | Strabismus | Bilateral astigmatism, left divergent squint (visual impairment); wears glasses |
| Mild optic nerve hypoplasia with cerebral visual impairment | Nystagmus | ||||
| Myopic astigmatism | |||||
| Endocrine assessment | GHD | Central diabetes insipidus since birth – on DDAVP | Central diabetes insipidus since birth – on DDAVP | GHD stimulation test not performed as hypotensive | GHD |
| Rest of endocrinology normal | Severe GHD | Severe GHD | Short stature with deceleration of growth rate | ||
| Premature thelarche – resolved | Premature thelarche – resolved | Adrenal insufficiency: peak cortisol 10.2 μg/dL on stimulation; rest normal | |||
| Premature pubarche | Premature pubarche | Cryptorchidism with bilateral orchidopexies | |||
| Other features | N/A | Hypoxic ischemic encephalopathy at birth – cooled | Percutaneous endoscopic gastrostomy tube in situ for unsafe swallow | Central sleep apnea | Hydrocephalus (VP shunt soon after birth) |
| Overhanging epiglottis | Central sleep apnea and hypoxia – no need for supplemental oxygen | ||||
| Percutaneous endoscopic gastrostomy tube in situ for unsafe swallow | Submandibular gland excision for excessive drooling | ||||
| Previous ovarian cyst on ultrasonography | Previous ovarian cyst on ultrasonography | ||||
| Diaphragmatic eversion | |||||
| Pierre Robin sequence without cleft palate. | |||||
| GH axis, age, y | 3.7 | 0.8 | 0.8 | 0.3 | 0.8 |
| Stimulation test | Glucagon | Overnight GH profile | Overnight GH profile | Not performed because of hypotension | Glucagon |
| Basal, ug/L | 0.6 | — | — | — | 2.4 |
| Peak, ug/L (NR > 6.7) | 6.4 | 4.8 (only 1 peak max 4.8) | 3.2 (only 1 peak max 3.2) | — | 3.7 |
| IGF-1, ng/mL (NR) | <25 | Undetectable | Undetectable | 31.9 (49–289) | <25 |
| Thyroid axis, age, y | 3.7 | 0.8 | 0.8 | 0.3 | 0.6 |
| fT4 pmol/L (NR) | 14.4 (9.8–19) | 13.8 (9.8–19) | 11.3 (9.8–19) | 18.8 (10.3–27) | 12.8 (9.8–19) |
| TSH mU/L (NR) | 2.8 (<6.0) | 1.9 (<6.0) | 1.1 (<6.0) | 2.87 (<6.0) | 1.5 (<6.0) |
| Adrenal axis | |||||
| Stimulation test (age, y) | Glucagon (3.7) | (0.8) | (0.8) | Synacthen (2.8) | Glucagon (0.7) |
| Peak cortisol, nmol/L | 989 | — | — | 281 | 488 |
| Random cortisol nmol/L (time) | Basal 252 (9 am) and 442 (12 noon at the end of the fast) | Random cortisol 1192 (9 am) | Random cortisol 748 (9 am) | — | 173 (7:30 pm) |
| Pubertal axis | Prepubertal | Prepubertal | Prepubertal | Prepubertal | Prepubertal |
| Endocrine medication (age at start, y) | GH (4) | GH (1) | GH (1) | HC (2.9) | GH (1) |
| DDAVP (from birth) | DDAVP (from birth) | GH (3.5) | |||
| MRI brain imaging | Normal | Progressive global cerebral hemisphere atrophy with relative preservation of the posterior fossa structures; small posterior pituitary and small optic nerves; thin corpus callosum | Mature right parieto-occipital infarct; generalized underdevelopment of the brain; posterior pituitary normal; thin corpus callosum | Normal | Right ventricular parietal VP shunt remains in situ; very thin corpus callosum; no evidence of obstructive hydrocephalus; bulky tectum and thin corpus callosum |
| Most recent results, age, y | 7.7 | 7.6 | 7.6 | 4.7 | 4.6 |
| Cortisol, nmol/L (time) | 339 (9 am) | 173 (11:45 am) | 159 (11:45 am) | — | 276 (9 am) |
| LH, IU/L (NR) | 0.2 (0.7–2.0) | — | 0.1 (0.7–2.0) | — | <0.1 (0.7–6.5) |
| FSH, IU/L (NR) | 0.6 (0.2–5.8) | — | 2.1 (0.2–5.8) | — | 0.7 (0.1–5.8) |
| PRL, mU/L (NR) | 131 (45–466) | — | 261 (45–466) | 194 (57–717) | |
| fT4, pmol/L (NR) | 16.6 (10.8–19.0) | 10.9 (10.8–19.0) | 10.0 (10.8–19.0) | 18.8 (10.29–27.03) | 13.8 (10.8–19.0) |
| TSH, mU/L (NR) | 2.8 (<6.0) | 2.5 (<6.0) | 2.4 (<6.0) | 1.22 (0.7–5.7) | 1.4 (<6.0) |
| IGF-1, ng/mL (NR) | 118 (64–345) | 102 (80–233) | 172 (80–233) | 65 (22–208) | 74 (47–231) |
| IGFBP-3, mg/L (NR) | 2.66 (1.6–6.5) | 3.73 (1.6–6.5) | 4.38 (1.6–6.5) | — | 1.60 (1.1–5.2) |
| Estradiol, pmol/L, or testosterone, nmol/L | — | Estradiol <44 | Estradiol <44 | — | Testosterone <0.69 |
Abbreviations: BMI, body mass index; DCDA, dichorionic diamniotic; DDAVP, desmopressin; fT4, free thyroxine; GERD, gastroesophageal reflux disease; HC, hydrocortisone; HIE, Hypoxic ischemic encephalopathy; IGFBP-3, insulin-like growth factor‒binding protein 3; IUGR, intrauterine growth restriction; LSCS, lower segment cesarean section; N/A, not applicable; PEG, percutaneous endoscopic gastrostomy; Prev, previous; PRL, prolactin; SDS, standard deviation score; VP, ventricular parietal; VSD, ventricular septal defect.