A daughter with weak muscles

The person of interest is a 3 year-old Caucasian girl born to unrelated 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 notable only for a routine fetal ultrasound observation of a slightly abnormal thickness in the ligament behind the head (nuchal translucency) 9 weeks gestation; evaluation of the heart by a fetal echocardiography at 19 weeks showed no cardiac or great vessel abnormalities. Chromosomes obtained by chorionic villus sampling (CVS) showed a normal chromosomes (karyotype) (46,XX).  The fetal movements and aminotic fluids during the pregnancy were reported by the mother as normal. The child was born at full term via caesarian section made necessary because of prior C-sections and the fact that this child was in a breach position. Apgars scores were normal (9 and 9 at 1 and 5 minutes respectively). The birth weight was six pounds and seven ounces. The physical exam at birth revealed long, thin fingers (arachnodactyly) and long feet, contractures of her fingers greater on the right side than the left (see photograph), a large port wine stain birthmark along the middle of her face (midline facial nevus flammeus), and low muscle tone or floppiness (hypotonia) with muscle less muscle present on her body than one would expect. 

At 3 months, the patient was evaluated for failure to thrive because of her poor weight gain and a drop in her growth velocity. She had also missed several milestones including the ability to hold her head up and the ability to sit up.  After an evaluation by a nutritionist and gastroenterologist, no obvious explanation was given for any of these observations.  She fed well but the diet was supplemented with extra calories though her weight gain did not improve.  A developmental evaluation at 8 months showed her gross motor skills – holding her head, crawling, moving around) -- at the 1 to 6 month level while her fine motor skills – pincer action of the finger and thumb, placement of small objects in cups, stacking cups --  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.  The physical exam showed she had flat feet, a “pigeon breast” sternum, inverted nipples seen in children with little subcutaneous fat, joints that could be extended more than normal, a small, recessed lower jaw, and eyes set slightly further apart than expected.   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 ridge under the skin vertically in the middle of her forehead, and normal teeth. The port wine stain had disappeared.  There were no droopy eyelids and her eye movements were normal. The whites of her eyes were egg schell blue.  She had contractures at the first joints of right second and third fingers. Examination of her muscles revealed decreased muscle mass in all the muscles on her frame and on her legs and arms. She was weak. The muscle tone was low and her reflexes were less brisk than usual.    

By echocardiogram, the aortic valve annulus was normal and no defects were seen.  The patient’s spine did not appear excessively curved or bent over.

The patient began to walk at 26 months.  Standing up from a sitting position the patient had to use her hands on the thighs to push herself into an upright position.  Her intellectual and language development were appropriate for age.  At 28 months, another echocardiogram showed a normal heart and vessels.  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.

X-rays of the cervical spine at 3 years were normal.  DNA analysis transforming growth factor beta receptor I and II genes and ACVR2A (ActR2A) and ACVR2B (ActR2B) genes showed wild-type sequence.   The ACVR1B gene showed a variant – read the DNA Analysis for a discussion of the procedure and the findings.