2.1 Patient A
Two affected siblings (shown in Figure 1) from first cousin Lur parents were referred to Madar Medical Genetics center. The proband was 3.7-year-old girl who was hospitalized immediately after delivery due to respiratory distress. Then, until age 1.5 she was repeatedly hospitalized because of recurrent respiratory infections and decreased consciousness, diagnosed as pneumonia. She had generalized hypotonia and moderate developmental delay since she has not acquired ambulation until the time of study, however, she was able to creep and crawl. She can stand up only by physical aid. The proband achieved limited level of communication, using few words to call her parents. Physical examination illustrated short stature, microcephaly, brachycephaly and synostotic trigonocephaly. The other clinical features include failure to thrive, short neck, dysmorphic face, triangular face, severe strabismus, myopia and amblyopia. The proband experienced three episodes of seizures following temperatures up to 40, phenobarbital administered in order to control seizures. She showed aggressive behavior and easy mood changes, injuring other infants by physically attacking them. Detailed clinical examination revealed specific facial dysmorphic features such as protruding ears, absent antihelical fold in left ear, sparce eyebrows, bulbus nose, wide nasal bridge, flat nasal tip as well as chubby cheeks. The auditory brain-stem responses (ABR) examination was normal at age 2. Furthermore, her parents complained about her increased appetite in addition to gastroesophageal refluxes. Neurological examination showed the extension of hallux during Babinski test, indicating upper motor neuropathy. However, unlike previously reported patients, no sign of sensory-autonomic neuropathy including sleep disturbances, apnea, decreased pain sensitivity, blood pressure, arrythmia was identified at the time of study. Laboratory findings indicated elevated levels of platelets and SGOT. The proband’s 2-year-old sister represented with similar clinical features of the proband (Figure 1). Furthermore, the affected sisters had silver-gray hairs and partial white patches on their skin. The younger sister’s hair was completely silvery or gray in majority of parts, while the proband’s hair was considerably darker. Similarly, white eyelashes and light iris were observed in both sisters. The proband had family history of grisclli appearance since her father and two of aunts and uncles represented with similar appearance. Since both siblings had griscelli phenotype in addition to developmental delay and neurological regression, the disorder was mistakenly diagnosed as phenylketonuria (PKU).