Clinical Genetics 1986: 29: 151-156

X-linked short stature with skin pigmentation: evidence for heterogeneity

of the Russell-Silver syndrome M. W. PARTINGTON

Division of Medical Genetics, Department of Paediatrics, Queen’s University, Kingston, Ontario, Canada

A family is described with a syndrome of short stature, abnormal pigmentation of the skin and mild facial dysmorphism. The short stature and pigmentary anomalies were more marked in the males than the females. The pattern of inheritance appeared X-linked. In 2 young brothers the clinical picture mimicked that of the Russell-Silver syndrome. It is suggested that the Russell-Silver syndrome is heterogeneous and that the criteria for its diagnosis need re-evaluation.

Received 16 April, revised, accepted f o r publication 7 October 1985

Key words; Facial dysmorphism; pigmentation of the skin; Russell-Silver syndrome; X-linked.

Although the Russell-Silver syndrome (RSS) was first described independently by Russell (1954) and Silver (Silver et al. 1953, Silver 1964), common features between the two were soon recognized (Black 1961, Ri- moin 1969) and the condition is now usually described (Smith 1982, Goodman & Gorlin 1983) and evaluated (Tanner et al. 1975, Angehrn et al. 1979) as a single syndrome.

Although the etiology is not known it is likely that genetic factors are important since the RSS has been found in both of monozygotic twins, in one of dizygotic twins, in sibs, half sibs and in parent and child (see Escobar et al. 1978 for review). Autosomal dominant inheritance with in- complete penetrance and a high frequency of new mutations has been suggested by several authors (Fuleihan et al. 1971, Gareis et al. 1971, Taussig et al. 1973, Escobar et al. 1978).

Some authors doubt that the RSS is a single clinical entity (Szalay 1963, Saal et al. 1984). At least 2 patients with the RSS have been found to have a 47,XXY karyotype (Bianchi et al. 1983) and one with trisomy 18 mosaicism (Chauvel et al. 1975). Good- man & Gorlin (1983) have suggested genetic heterogeneity, at least among those patients with the “Russell variant” (i.e. without asymmetry of the body). In support of this view a boy is presented with many features of the RSS but who also has unusual pig- mentation of the skin. Findings in the rest of the family point to X-linked inheritance.

Case Reports

The Family The family lives in eastern Ontario and is of Dutch descent. The pedigree is shown in Fig. 1.

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I I

3 4 16 17

m

m B Russell-Silver syndrome @ Short adult stature c l60cm

0 Skin pigmentation

Fig. 1. Pedigree of the Family

The proband (IV-9 in Fig. 1) was born in 1977, at term, following a normal preg- nancy and a spontaneous vertex delivery. The Apgar score was 9, the birth weight 1890 g, crown-heel length 45 cm and the occipito-frontal circumference (OFC) was 32 cm. The neonatal period was uneventful except for a rapid increase in head size; he was seen by a neurosurgeon and observed in hospital for hydrocephalus for two weeks.

During infmcy there were many minor infections and growth was slow. At 15 months he developed a pertussis-like illness with diarrhea and was seen by the author for the first time. Both height (68.5 cm) and weight (6.57 kg) were below the third centile but the OFC (47 cm) was about average for his chronological age. The head looked disproportionately large with a wide-open anterior fontanel, frontal bossing and a small, pointed chin giving the face a triangu- lar appearance (Fig. 2). There was an irregu- lar area of brown pigmented skin about 1 cm across on the left thigh. Mental and motor development were normal. The bone age was 12 months. A skull X-ray suggested hydrocephalus which was not confirmed by a CAT scan. Chromosome studies showed a

normal 46,XY karyotype with no increased frequency of gaps and breaks and a normal rate of sister chromatid exchanges.

Over the next 6 months he developed several more small brown pigmented spots on the skin of the trunk and limbs. By 23 years diffuse brown pigmentation was noted over the right lower trunk together with a few small achromic spots. Thereafter, all 3 types of pigmentary change increased in size and extent covering most of the trunk and limbs (Fig. 3) but sparing the face. The nip- ples became dark brown. The achromic spots did not tan in sunlight and easily be- came sunburned.

Growth continued at a normal rate but both height and weight were 2.5 standard deviations below the mean for age. At age 8 years and 10 months his height was 112 cm, weight 16.3 kg and OFC 51 cm. At the age of 2 years he developed asthma which required more than 20 short-term admis- sions to hospital over the next five years.

The proband’s brother (IV-10) was born in 1980. The pregnancy was normal but slow fetal growth was noted in the third trimester and labour was induced a t 38 weeks gestation. There was an unassisted

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Fig. 2. Proband (left), aged 6 years, with his brother, age 3: years and their mother. Inset, proband at age 34 years and brother at age 6 months. Note tri- angular appearance of the face in both boys and prominent upper jaw in the mother.

vertex delivery. The placenta was noted to be small. The Apgar score was 8, the birthweight (1950 g), length (44 cm) and OFC (32 cm) were all below the third centi- le. A triangular face was evident at birth. He grew in stature somewhat faster than in weight so that at 4 t years his height (98 cm) was between the third and tenth centile but his weight (12.4 kg) was below the third centile; the OFC (48 cm) was at the third centile. His health was good except for one brief asthmatic episode. No abnormal skin pigmentation was observed until the age of one year when a brown spot was seen on the right wrist. Subsequently several more dark brown spots appeared together with

diffuse patches of brown pigmentation on the trunk and thighs and many small circu- lar achromic spots, 3 of them more than 2 cm in diameter. These did not tan and be- came sunburned easily.

The mother (111-12), born in 1947, was a schoolteacher and in good health. Her height was 160 cm. She had about 50 small round brown pigmented spots distributed over the arms and trunk. Her next youngest sister (111-13), born in 1948, was 158 cm tall and had about 50 round brown spots on her trunk and arms. In addition she had an irregular 3.5 cm patch of diffuse brown pigmentation on her back which contained five or six small circular achromic spots.

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Fig. 3. Proband, age 6 years, showing dark irregular pigmented spots, diffuse pigmentation, achromic spots and diffuse depigmentation in the groin. Note sharply demarcated diagonal upper border to the patch of pigmentation on the right trunk and the darkened nipple.

She suffered from migraine and had had one grand ma1 seizure at the age of 37. Her 7-year-old twin daughters had no skin pigmentation. Another sister (111- 14), born in 1950, was 157 cm in height and had about 30 brown spots of which 2 were more than 1.5 cm in diameter, on the skin of the trunk and limbs; the distribution on the trunk seemed to follow the dermatomes. There were also 6 oval achromic spots on the trunk. The facial appearance of these 3 sis- ters was very similar with a somewhat large mouth and prominent upper jaw (Fig. 2). They all looked quite different from their other 4 sisters none of whom had spots of pigmentation and all of whom were over 168 cm in height. All the brothers were over 180 cm in height and had no abnormal pig- mentation.

The maternal grandmother (11-4), born in 1918, was 170 cm in height and had no abnormal skin pigmentation. Her sibs live in The Netherlands. She had one brother

(11-16), aged 55, who was a twin; his female cotwin died at birth. His birthweight was about 1 kg and he reached no more than 158 cm in height as an adult. This man had not married. A good family photograph showed bitemporal balding, protruding ears, a pointed jaw and a triangular face. His mother (I-2), seen on the same photo- graph, had an adult height of about 158 cm.

The height of the proband’s father (III- 9) was 187 cm and his paternal grandfather (11-3) was 180 cm.

Discussion

The index case in this family had many of the features of the RSS including pre- and postnatal growth retardation, frequent in- fections in infancy and a triangular face. The OFC was normal but hydrocephalus was suspected in the neonatal period and again at 15 months at which age he had one cafe-au-lait spot. A diagnosis of the RSS

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was made. However, over the next year, as the skin lesions increased in variety and extent and the correlation emerged between skin pigmentation and relative short stature in his mother and her sisters, the diagnosis was revised to a single gene X-linked dis- order. A recurrence risk of 25% was given to the parents (50% if the child were a boy). It was clear, at birth, from the growth retar- dation and triangular face, that the younger brother had the same condition. He grew somewhat taller than his brother (though the OFC was smaller) and, in due course, developed the same 3 pigmentary changes of his skin.

These pigmentary changes are quite dif- ferent from the one or two cafe-au-lait spots found in about one third of patients with the RSS. However, Silver (1964) has de- scribed a 9-year-old girl (Case 5) who had “several large cafe-au-lait spots . . . over the mid back, along the medial aspect of the right forearm and over the palm of the right hand.” This suggests distribution along a dermatome similar to that found in 111-14.

The present family seems to have a syn- drome of short stature, pigmentary anomal- ies of the skin and mild facial dysmorphism with more severe expression of the short stature and pigmentation in the males than in the females. In the males the clinical pic- ture mimics that of the RSS. X-linkage seems probable but sex-influenced autoso- ma1 dominant inheritance cannot be ex- cluded. X-linkage has not been suggested for the RSS previously but several pub- lished pedigrees are at least consistent with this pattern of inheritance. (Silver & Gru- skay 1957, Warkany et al. 1961, Callaghan 1970, Fuleihan et al. 1971, Taussig et al. 1973, Escobar et al. 1978).

These findings suggest that the RSS is, indeed, heterogeneous and support the plea of Saal et al. (1984) “that the diagnostic criteria for the Russell-Silver syndrome should be re-evaluated.’’

Acknowledgments

I wish to thank Dr. Darrell Tompkins for the chromosomal studies on the proband and the family for their cooperation.

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Address: M . W Partington, M.B., Ph.D. Division of Medical Genetics Department of Paediatrics Queen's University Kingston, Ontario K7L 3N6 Canada