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Dysmorphism, variable overgrowth, normal bone age, and severe developmental delay: a “Sotos-like” syndrome?
  1. J Amiel1,
  2. L Faivre1,
  3. L Wilson2,
  4. M Le Merrer1,
  5. A Munnich1,
  6. R Winter2,
  7. S Lyonnet1,
  8. V Cormier-Daire1
  1. 1Département de Génétique, Hôpital Necker-Enfants Malades, 149 rue de Sévres, 75743 Paris, France
  2. 2Mothercare Department of Paediatric Genetics, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
  1. Correspondence to:
 Dr Cormier-Daire, Département de Génétique, Hôpital Necker-Enfants Malades, 149 rue de Sévres, 75743 Paris, France;
 cormier{at}necker.frCorrespondence to:
 Dr M Stumm, Institut für Humangenetik, Universitätsklinikum, Leipziger Strasse 44, 39120 Magdeburg, Germany;
 Markus.Stumm{at}medizin.uni-magdeburg.de

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Sotos syndrome (MIM 117550) is an overgrowth syndrome first described by Sotos et al1 in 1964 with over 200 cases reported to date. The syndrome is characterised by pre- and postnatal overgrowth, macrocephaly, advanced bone age, and distinctive facial features.2 In a review of 79 patients diagnosed as Sotos syndrome, Cole and Hughes3 showed that the overall gestalt was as efficient as clinical and radiological criteria for the diagnosis. The vast majority of cases are sporadic. Concordant and discordant monozygotic twins have been reported.4,5 In rare instances, familial cases with autosomal dominant or autosomal recessive inheritance have been suspected and chromosomal rearrangements have also been reported.4,6 However, the aetiology of Sotos syndrome remains unknown. A hypothalamic origin was first suspected but extensive endocrinological testing failed to show significant anomalies. More recently, chromosomal uniparental disomy has been ruled out.7 Here, we report on five unrelated cases with a Sotos facial gestalt, severe developmental delay, moderate to absent overgrowth, and normal bone age. We propose a separate Sotos-like syndrome.

CASE REPORTS

Case 1

Case 1, a male, was the third child of healthy, non-consanguineous parents, aged 31 and 33 years at the time of birth. The mother's height was 1.57 m (25th centile) and the father's 1.72 m (between the 25th and 50th centile). Amniocentesis was performed for at risk maternal serum screening and fetal chromosomes were normal 46,XY. Bilateral vesicoureteral reflux was diagnosed prenatally and surgically repaired at 9 months of age. He was born at term with normal birth parameters (birth weight 3360 g, 25th centile; length 51 cm, 50th centile; OFC 35 cm, 50th centile). He had hypotonia and psychomotor delay (sat at 12 months, walked at 24 months, no words at 24 months). He was first investigated at 9 months; hypsarrythmia was diagnosed and treated with Vigabatrin. He was admitted to hospital eight days later with Streptococcus pneumoniae meningitis. When first seen, at 22 months of age, growth was in the normal range (weight 14 kg, 75th centile; height 90 cm, 75th centile; OFC 50.5 cm, 75th centile). Facial features included a long face with a pointed chin, dolichocephaly, a high forehead with receding frontal hairline, fine hair, mild hypertelorism, convergent strabismus, and a high arched palate (fig 1A, B). The hands and feet were large with flat, brittle, deep set nails (fig 1C, D). Examination of the skin showed loose skin on the extremities and two punctiform scars across one arm. He stands with kyphosis, bent knees, and pes planus. Peripheral reflexes were brisk. Fundi were normal.

Figure 1

Case 1. (A) Note the long face with pointed chin, high forehead with receding frontal hairline, fine hair, mild hypertelorism, and convergent strabismus. (B) Note dolichocephaly. (C) Note large feet and flat, brittle, deep set nails. (D) Note large hands and loose skin

EEG showed hypsarrythmia and MRI of the brain showed a right parietofrontal cavity, a cyst of the septum pellucidum, and mild ventriculomegaly. At 22 months of age, bone age was 2 years for carpal bones, phalanges, and metacarpals according to Greulich and Pyle. Supernumerary epiphyses were present at the base of the second and third metacarpals. High resolution chromosomes were normal (46,XY) on lymphocytes with no fragile site on the X chromosome.

Case 2

Case 2, a male, was the third child of healthy, non-consanguineous parents aged 38 and 43 years at the time of birth. The mother's height was 1.70 m (90th centile) and the father's 1.87 m (>97th centile). The mother's OFC was 57 cm (97th centile). The older brother's and sister's heights were above the 97th centile (1.81 m at 14 years and 1.78 m at 13 years, respectively). Amniocentesis for maternal age showed normal fetal chromosomes, 46,XY. The mother had hypertension in the third trimester of the pregnancy. He was born at term with normal birth parameters (birth weight 3570 g, 75th centile; length 54 cm, 90th centile; OFC 36.5 cm, 75th centile). There was a unilateral cleft lip and upper gum, feeding difficulties, hypotonia, hyperbilirubinaemia, and hypoglycaemia at birth. He showed psychomotor delay (sat at 12 months, walked at 24 months, no words at 6 years). When first seen, at 26 months of age, growth was above the mean (weight 16 kg, 90th centile; length 100 cm, 97th centile; OFC 54.5 cm, >97th centile). Facial features included a long face with pointed chin, dolichocephaly, a high forehead with receding frontal hairline, fine hair, mild hypertelorism, epicanthic folds, and downward slanting palpebral fissures (fig 2A, B). The hands and feet were large with flat, brittle, deep set nails (fig 2C, D). The skin was velvety. He stands with kyphosis, bent hips and knees, and pes planus. Fundi were normal. At 6 years of age, height is above the 97th centile, weight is between the 90th and 97th centile, and OFC is above the 97th centile.

Figure 2

Case 2. (A) Note the long face with pointed chin, high forehead with receding frontal hairline, fine hair, mild hypertelorism, epicanthic folds, downward slanting palpebral fissures, and repaired cleft lip. (B) Note dolichocephaly. (C) Note large hands. (D) Note large feet and flat, brittle, deep set nails.

MRI of the brain showed mild ventriculomegaly. At 26 months of age, bone age was 2 years 8 months according to Greulich and Pyle. Pseudoepiphyses were present at the base of the second and fifth metacarpals. High resolution chromosomes were normal (46,XY) on lymphocytes with no fragile site on the X chromosome. Auditory evoked potentials and abdominal ultrasound were normal.

Case 3

Case 3, a male, was the first child of healthy, non-consanguineous parents aged 28 and 42 years at the time of birth. The mother subsequently had two miscarriages. The mother's height was 1.60 m (50th centile) and the father's 1.72 m (25th centile). Case 3 was born at 33 weeks of gestation (birth weight 2100 g, 50th centile; length 44 cm, 50th centile; OFC 32 cm). He had ventricular septal defect and a patent ductus arteriosus that closed spontaneously. Psychomotor development was delayed (sat at 14 months, walked at 3 years, three words at 2 years 10 months). At 11.5 years of age, height and weight were on the 97th centile and OFC >97th centile. He attended normal school with two years delay. Facial dysmorphic features included a long face with a pointed chin, a high forehead with receding frontal hair line and fine hair (fig 3A, B). The hands and feet were large (>97th centile) with flat, deep set nails that required surgery.

Figure 3

(A, B) Case 3. Note the long face with pointed chin, high forehead with receding frontal hair line, and fine hair. (C, D) Case 4. Note the long face with pointed chin, high forehead, hypertelorism, epicanthic folds, and downward slanting palpebral fissures. Facial asymmetry is not a feature.

Brain CT scan showed mild ventriculomegaly. At 3 years of age, bone age is 3 years 6 months according to Greulich and Pyle. High resolution chromosomes were normal (46,XY) in lymphocytes. Fragile X was ruled out by molecular testing.

Case 4

Case 4, a female, was the first of two children of healthy, non-consanguineous parents aged 30 and 22 years at the time of birth. The mother's height was 1.53 m (10th centile) and the father's 1.74 m (50th centile). The mother had two healthy children from a previous union. She was born at term after an uneventful pregnancy with birth parameters as follows: birth weight 3140 g, 50th centile; OFC 36.5 cm, 90th centile (length not recorded). Psychomotor development was slow and she was hyperactive with temper tantrums and obsessional behaviour (sat at 9 months, walked at 18 months, no words at 3 years 10 months). Seizures occurred at 7 months of age and were treated by carbamazepine. Patent ductus arteriosus was surgically repaired at 1 year. Growth followed the 50th centile until the age of 3.5 years. Growth acceleration started at that age with height on the 90th centile; weight and OFC were above the 97th centile at 5 years of age. Facial dysmorphic features included a long face with a pointed chin, a high forehead, dolichocephaly, hypertelorism, epicanthic folds, downward slanting palpebral fissures, strabismus, a low nasal bridge, and a narrow, high palate (fig 3C, D). Extremities were large with bilateral 2-3 syndactyly of the toes. Examination of the skin was normal.

A brain CT scan and MRI showed mild ventriculomegaly. Electroencephalography was normal. At 3 years 10 months of age, bone age was between 3 years and 3 years 8 months according to Greulich and Pyle. Blood karyotype showed normal chromosomes (46,XX) in lymphocytes. Fragile X was ruled out by molecular testing.

Case 5

Case 5, a male, was the second child of healthy, unrelated parents. Both parents were of average stature but their heights were not recorded. He was born at term with a normal birth weight (3300 g). At 21 months of age, growth was in the normal range (weight 12.9 kg, 75th centile; height 86.4 cm, 75th centile; OFC 52.1 cm, 97th centile). Psychomotor development was delayed (standing with support, one word). Facial dysmorphic features included dolichocephaly, a high forehead with frontal bossing and receding frontal hair line, a long face with a pointed chin, downward slanting palpebral fissures, strabismus, a high palate, and a unilateral ear pit. He had large hands and feet. The skin was lax and he had three café au lait patches.

Brain CT scan showed partial agenesis of the corpus callosum. Blood karyotype showed normal chromosomes (46,XY) on lymphocytes and fragile X was ruled out by molecular testing. At 21 months of age, bone age was 2 years 8 months according to Greulich and Pyle while his distal radial epiphysis was not yet visible.

DISCUSSION

Here we report five unrelated patients with the combination of similar and distinctive facial features, loose skin on the extremities with brittle, deep set nails (3/5), moderate to severe developmental delay, moderate to absent overgrowth, normal bone age, and mild ventriculomegaly (tables 1 and 2). The five cases we report are sporadic and no consanguinity was observed. There was no known exposure to drugs or toxins during the pregnancies. Fragile X syndrome was ruled out in all patients and there was no identified chromosomal rearrangement on blood karyotyping.

Table 1

Clinical and radiological findings in the five reported cases and four published cases discussed as “Sotos-like” syndrome

Table 2

Facial dysmorphic features in the five reported cases and four published cases compared to distinctive facial features in a series of patients with Sotos syndrome*

Features consistently observed in our patients have been described in Sotos syndrome, namely facial gestalt, large extremities, brittle, deep set nails, and loose skin. Similarly, mild, non-specific ventriculomegaly and corpus callosum agenesis are frequently found in Sotos syndrome.8 Therefore, although the five patients have the Sotos syndrome facial gestalt, they share features that make Sotos syndrome unlikely, namely absence of overgrowth and macrocephaly at birth, growth acceleration of late onset that remained moderate (from 26 months to 6 years of age, patients 2-4), normal bone age, and severe psychomotor delay. Macrocephaly-cutis marmorata-telangiectatica congenita syndrome was considered in case 4 and ruled out because of absent overgrowth and macrocephaly at birth, absence of segmental overgrowth and hydrocephalus, and normal skin examination.9 Finally, none of the syndromes included in the differential diagnosis of Sotos syndrome seem satisfactory, namely Weaver-Smith (MIM 277590), autosomal dominant macrocephaly (MIM 153470), and Zonana-Bannayan (MIM 153480) syndromes.

Sotos syndrome remains of unknown aetiology and may have been overdiagnosed.3 Reviewing published reports, we found four cases which may be similar to the cases reported here. Suzuki et al10 reported a male patient diagnosed as Sotos syndrome who showed the combination of increased height, large extremities, normocephaly, hypsarrythmia, and moderately advanced bone age (table 1). Because of the ethnic origin, dysmorphic features are difficult to appreciate. Nevertheless, the patient showed a high forehead with receding frontal hair line, downward slanting palpebral fissures, and a high arched palate (table 2). Robertson and Bankier11 reported three unrelated cases with the combination of an overall Sotos gestalt, macrocephaly, moderate to absent overgrowth, developmental delay, and normal bone age (tables 1 and 2). They put emphasis on symptoms suggestive of a connective tissue disorder, namely cutis laxa, joint hypermobility, and vesicoureteric reflux. Cole and Hughes3 reviewed 79 cases diagnosed as Sotos syndrome and categorised 22 patients as “definitely not Sotos” (28%). Among this group, two sisters were described as combining “significant developmental delay and characteristic facies with normal bone age and chromosomal analyses”. They may represent the Sotos-like syndrome. Goldstein et al12 reported two unrelated patients with overgrowth, macrocephaly, advanced bone age, developmental delay, nystagmus, and dysmorphic facial features with epicanthic folds, a depressed nasal bridge, and anteverted nares. The authors raised the question of a variant of Sotos syndrome. We believe that they represent a distinct entity from the cases we report.

In the absence of definitive genetic tests, one should be cautious with the diagnosis of Sotos syndrome. We propose a Sotos-like syndrome for the association of Sotos facial gestalt, moderate overgrowth and macrocephaly, severe developmental delay, and normal bone age. We do not know whether the Sotos-like syndrome is allelic to Sotos syndrome or genetically distinct if of genetic origin, the cases we report being sporadic. It would be of interest to know whether other clinicians have encountered similar patients and experienced the same diagnostic difficulties.

Acknowledgments

We thank the families for their cooperation and Professor Brunelle for reviewing the patients' x rays and for helpful discussion.

REFERENCES

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Footnotes

  • I Chudoba,MetaSystems Inc, Altlussheim, Germany

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