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Editor—We present the clinical histories and physical findings in two unrelated, severely mentally retarded males, now 14 and 11 years old.
Patient 1, a male, was born as the second and youngest child of healthy, unrelated Flemish parents with normal family histories. Pregnancy and delivery at 38 weeks' gestation were normal. Birth weight was 3200 g, length 47 cm, and head circumference 34 cm. Immediately after birth a number of dysmorphic signs were noted by the paediatrician, including facial oedema with ptosis of both eyelids, temporal flattening, hypertelorism, webbed neck, broad thorax with widely spaced, small, inverted nipples, shallow scrotum, and testes in the inguinal canal. The hands were broad and short with permanent oedema on the dorsum and the skin was loose and hyperextensible, especially on the arms. The diagnosis of Noonan syndrome was considered. Cardiac and renal echography was normal. Prometaphase chromosome studies on a peripheral blood lymphocyte culture showed a 46,XY normal male karyotype after G and R banding. Except for excessive weight loss, down to 2600 g, no major problems were noted in the neonatal period. In the first two years of life mild psychomotor retardation was noted with discrete hypertonia of the lower limbs. He started to walk without support on tiptoes at the age of 19 months. At the age of 2 years mental age was 15 months on the Bayley Developmental Scale.
At the age of 3 years, the first episodes of epileptic attacks were noted with variable clinical presentation of the grand mal, petit mal, and myoclonic types. Seizures were resistant to anti-epileptic therapy and, from that age onwards, severe behavioural problems were noted with chaotic and destructive tantrums. EEG was diffusely disturbed with generalisation from a right frontotemporal focus. Brain MRI showed diffuse pachygyria, most evident in the frontal lobes. Ophthalmological examinations and x ray skeletal survey were normal. At that age, weight was 14.5 kg (25th centile), length 91 cm (25th centile), and head circumference 48 cm (3rd centile). At the age of 6 years mental retardation was severe (mental age of 2 years, SON-R)F. Neurological examination showed fine motor coordination problems and mild signs of spastic paraparesis. He walked without support with 20-30° extension deficit of both knees and 20° extension deficit of both elbows. Now, at the age of 11 years, he is severely mentally retarded with no progress in psychomotor development and has persistent epileptic fits.
Figs 1A and 2A and C illustrate the craniofacial dysmorphism, the general habitus, and the chaotic behaviour. Craniofacial appearance is distinct with oedema, narrowing of the frontal part of the skull, arched eyebrows, trigonocephaly, bilateral ptosis, hypertelorism, a large mouth with a fine upper lip and everted lower lip, prominent upper central incisors, posteriorly rotated ears with underdeveloped antihelix, and a high arched palate. The neck is broad, short, and webbed with a low posterior hairline. The upper part of the thorax is narrow, and the nipples are widely spaced, hypoplastic, and inverted. The hands are broad with tapering fingers.
Extensive metabolic screening has been performed over the years with normal results. Chromosome studies on a fibroblast culture after skin biopsy of the left upper arm were normal. Genital development is prepubertal with small testes (5 ml) in the inguinal canal. Hormone studies (LH, FSH, and plasma testosterone) showed normal prepubertal results. Height, weight, and head circumference are on the 3rd centile for age.
Patient 2, a male, is the third child of a non-consanguineous European couple. He has two normal brothers, 16 and 9 years old respectively, and a 7 year old normal sister. Pregnancy was unremarkable. Birth weight was 3200 g. He had facial oedema and it was noted that he had significant redundant skin over the nape of the neck. Furthermore, he had significant weight loss in the neonatal period, losing more than 500 g in weight. He did not have any feeding difficulties. He crawled at 9 months and walked on tiptoes by 18 months. He had mild speech delay and his development was reasonable until the age of 5 years when he began to have persistent seizures which so far are not totally controlled with anti-epileptic medication. A brain CT scan showed pachygyria of the frontal lobes. His mental development deteriorated from the onset of the seizures and currently his mental function is at the 5 year level. In the past he has had surgery for squint, as well as for ptosis. Bilateral vesicoureteral reflux with hydronephrosis was also diagnosed in infancy and required bilateral ureteral reimplantation.
At present (figs 1B and 2B, D), height is 136 cm (3rd centile is 143 cm) and head circumference 53.5 cm (25th centile). Craniofacial appearance is distinct with thick hair, low frontal hairline, significant narrowing of the frontal part of the skull, facial oedema, bushy, arched eyebrows, a broad root and bridge of the nose, and persistent bilateral ptosis. He has a long, flat philtrum, a thin upper lip, micrognathia, and everted lower lip. The palate is high arched and the upper central incisors are prominent. The ears are protuberant, posteriorly rotated, and with underdeveloped antihelices. The neck is broad, short, and webbed with a low posterior hairline. The upper part of the thorax is relatively small with broadly spaced, hypoplastic, and inverted nipples. The hands are broad with proximally placed thumbs. He is able to walk without support, with 20-30° extension deficit of the knees and some difficulties in fully extending the elbows.
Chromosome studies on a peripheral blood lymphocyte culture showed a 46,XY normal male karyotype on G banding.
The two unrelated males present, as described above, a remarkably similar MCA/MR syndrome and their clinical history is also identical. Patient 1 has been followed in Leuven since the neonatal period and patient 2 has been followed in Auckland. The striking resemblance between the two patients was recognised almost by coincidence on the occasion of the exchange of data on patients with distinct but hitherto unidentified MCA/MR syndromes. As described, their craniofacial appearance is particularly similar. Both males presented at birth with facial oedema, and it is still evident at their present respective ages of 14 and 11 years. The significant weight loss in both patients in the neonatal period indicates that they had more generalised fetal oedema and, especially in patient 1, in the postnatal period the skin was loose and hyperextensible, most evident on the arms. Based on the combination of facial oedema, ptosis of the eyelids, webbed neck with low posterior hairline, and broad thorax with widely spaced nipples, the diagnosis of Noonan syndrome was considered in patient 1.1 However, the clinical follow up and evolution with age were not compatible with this diagnosis. Another remarkable finding in both males was their lack of psychomotor evolution with age. At the respective ages of 3 and 5 years, epileptic attacks began, which so far cannot be controlled despite a great variety of anti-epileptic medication. In both patients brain CT and MRI scan showed pachygyria, most pronounced in the frontal lobes. Up to the start of the complex epileptic fits, psychomotor development was only mildly to moderately retarded, but since the onset of seizures mental development has deteriorated. At the present time, both males are severely to profoundly mentally retarded and, especially in patient 1, major behavioural problems are now present. Also the general habitus of both males is identical. Whereas no specific neurological abnormalities are present, except walking on tiptoes with mild signs of spastic diplegia at a young age, both males walk independently but with 20-30° extension deficit of both knees, and both have difficulties in fully extending their elbows.
The MCA/MR syndrome present in these two males thus combines the following major symptoms: (1) distinct facies with oedema and notable postnatal weight loss; (2) broad and webbed neck; (3) hypoplastic, inverted nipples; (4) limited extension of elbows and knees resulting in a characteristic general habitus; and (5) complex epilepsy in early childhood with deterioration of mental development and pachygyria on brain imaging.
The authors thank Dr N Goeman (Paediatric Department, University Hospital Leuven, Belgium) and Dr E Carmichael (Paediatrician, Hamilton, New Zealand) for referring the patients.