A Case of Hypomyoplasia with Marfanoid features

The proband is a 3 year-old Caucasian girl born to non-consanguineous parents.  The mother was 41 years old, the father 50 at the time of conception.  The parents have two older healthy children.  The pregnancy was remarkable only for a fetal ultrasound observation of nuchal translucency of 3 mm at 9 weeks gestation; evaluation by a fetal echocardiography at 19 weeks showed no cardiac or great vessel abnormalities. Chromosomes obtained by chorionic villus sampling showed a normal karyotype (46,XX).  Fetal movements and aminotic fluids were reported as normal. The child was born at full term via caesarian section secondary to repeat sections and breach presentation. Apgars were 9 and 9 at 1 and 5 minutes respectively. The birth weight was six pounds and seven ounces. The physical exam at birth revealed arachnodactyly and long feet, digital contractures (right greater than left, see photograph), a midline facial nevus flammeus, and hypotonia with marked hypoplasia of skeletal muscles.

At 3 months, the patient was evaluated for failure to thrive, a fall in growth velocity, and a delay in gross motor function without causative findings.  The patient fed well and the diet was supplemented with extra calories with no improvement in weight.  A developmental evaluation at 8 months showed her gross motor skills at the 1 to 6 month level while her fine motor skills were placed at the 8 month level.  Her weight fell to below the 1^st percentile for age while head circumference fell from the 45^th percentile at birth to the 25^th percentile by age 8 months.  She was reevaluated at 16 months of age: the patient did not crawl or roll; she could stand with support.  She was at the 5^th percentile for height.  Noted was bilateral pes planus, pectus carinatum, inverted nipples, hyperextensibility of multiple joints, hypognathia and hypertelorism with an outer canthal distance of 7.8 cm and an inner canthal distance of 2.8 cm.   Her skin had normal texture, tension and wound healing. Examination of the head revealed normally placed and well-formed ears, bifid uvula with intact hard and soft palate, a small metopic ridge, and normal teeth. The nevus flammeus was not evident.  There was no ptosis and her extraocular movements were normal. The sclerae were blue.  She has contractures at the proximal phalangeal joints of right second and third digits. The thumb sign was negative.  Her motor examination revealed decreased bulk in all appendicular and axial muscles, strength 1/5, low tone and diminished reflexes throughout.    By echocardiogram the aortic valve annulus measured 10.4 mm with no wall or vessel defects or valvular prolapse.  The patient had no evidence of kyphoscoliosis.

The patient began to walk at 24 months standing up from a sitting position with a positive Gower sign.  Her neurocognitive development was appropriate for age.  At 28 months the aortic valve annulus measured 11 mm.  Her weight was 20 pounds, below the 1^st percentile, her head circumference at the 25^th percentile, her height between the 10^th and 25^th percentile.  Her strength was judged 1-2 on a scale of 5, with diminished reflexes.  The remainder of the exam was unchanged and the history unremarkable.  On her third birthday she weighed 21 pounds. She walked in a “hip waddle” fashion.  Her language development was placed at 4.5 years.

An echocardiogram at 4.4 years of age was normal.  Her weight was 26 pounds.

X-rays of the cervical spine at 3 years were normal.  Standard hematologic and serum chemistries, CPK and lactic acid were normal.  7-hydrocholesterol, pristanic and phytanic acids, carnitine and acylcarnitine, plasma amino acids and urinary organic acids were normal.  Analysis for disorders of glycosylation was negative.  Mutational analysis of the exons and adjacent intronic DNA of the TGFBeta Receptor I and II and ACVR2A (ActR2A) and ACVR2B (ActR2B) genes showed wild-type sequence. The ACVR1B gene had an unreported variant. Investigation of the parents for the variant is pending.