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).