Abnormal facial appearance, body asymmetry, limb deformities, and internal malformations


  • How to Cite this Article: Oudesluijs G, Simon MEH, Burggraaf RHJ, Waterham HR, Hennekam RCM. 2012. Abnormal facial appearance, body asymmetry, limb deformities, and internal malformations. Am J Med Genet Part A 158A:292–297.


We describe a newborn girl with multiple congenital anomalies and abnormal phenotype comprising underdeveloped corpus callosum with ventriculomegaly, chorioretinal atrophy, pulmonary arterial hypertension, annular pancreas, horseshoe kidney, asymmetric limb and chest anomalies, spinal segmentation defects, hypertrichosis, and unusual face with large anterior fontanel, high anterior hairline, broad forehead, mildly underdeveloped midface, hypertelorism, depressed nasal bridge, short and upturned nose, large mouth, retrognathia, and large and malformed ears. Work-up included cytogenetic studies of lymphocytes and skin fibroblasts, subtelomere Multiplex Ligation-dependent Probe Amplification (MLPA), whole-genome oligo-array, and molecular analysis of SETBP1 and NSDHL: no abnormalities were found. Mucopolysaccharide urinary excretion was elevated. Results of metabolic studies for sterol and peroxisomal abnormalities in fibroblasts were normal. Additional electronic microscopy studies in skin fibroblasts did not show evidence for storage in fibroblasts or lysosomal changes. Nosologic considerations allowed exclusion of Schinzel–Giedion and Urioste syndrome. This condition seems not to have been described before; a segregating Mendelian mutation is assumed. © 2011 Wiley Periodicals, Inc.


Recently, we evaluated a newborn girl with severe limb and other skeletal, brain and internal organ anomalies, chorioretinal atrophy, hypertrichosis, and an unusual face in whom we were unable to diagnose a known entity despite extensive investigations. This patient may represent a hitherto undescribed entity.


The proposita was the first child of healthy, non-consanguineous Dutch parents. The parents have no malformations. The father and father's sister have a high forehead and prominent supra-orbital ridges. A son of a paternal uncle has a single kidney. A maternal uncle had hypertrichosis at birth. Family history was otherwise non-contributory. At the time of birth, maternal and paternal age was 26 and 31 years, respectively. Mother considered fetal movements to have been reduced. Second trimester sonography showed changes suggestive of a Dandy–Walker malformation, and abnormalities of limbs and thorax. Delivery was spontaneous at equation image weeks. Weight at birth was 2,218 g (5th centile). Head circumference (OFC) and length at birth were not recorded, but at 2 days OFC was 33.0 cm (25th centile). Apgar scores at 1, 5, and 10 min were 6, 9, and 9, respectively. The girl had an abnormal appearance (Figs. 1 and 2): A large anterior fontanel, high anterior hairline, broad forehead, bitemporal narrowing, mildly underdeveloped midface, hypertelorism, depressed nasal bridge, short and upturned nose, large mouth, retrognathia, and relatively large ears with flat crus superior and inferior. Her neck appeared short and the thorax was asymmetric, the right side being smaller than the left. She had disproportionately short limbs with left side of body appearing larger than the right. She had hypertrichosis of the arms (especially slightly above the elbows), thighs and buttocks. There were contractures at the elbows. There were no Blaschko-linear pigmentations of the skin. Hands showed a single palmar crease. On the right the thumb was distally placed and the thenar eminence was underdeveloped. The second digit lacked a nail with a small skin dimple. There was syndactyly between the fourth and fifth digits, which were underdeveloped. Metacarpal bones IV and V were short. The left thumb was proximally implanted, the second digit was small and there was clinodactyly of the third finger. The fourth and fifth digits of her right foot were small and without nails. Her left foot showed nail hypoplasia of all toes. She had female genitalia, with the right labium majus smaller than the left. The anus was slightly dorsally placed.

Figure 1.

Face, arms, and abdomen. Note, abnormal facial appearance, high anterior hairline, broad forehead, hypertelorism, short and upturned nose, large mouth, short neck, asymmetric thorax, hypertrichosis and contractures of the elbows, disproportionately short limbs with left side of body appearing larger than the right.

Figure 2.

Right hand (A), left hand (B), right foot (C), and profile (D) of the present proposita. Right hand: please note the distally placed thumb, nail aplasia of the second finger, syndactyly between the small fourth and fifth digits, and short IV and V metacarpal bones. Left hand: please note the proximally implanted thumb, small second digit, and clinodactyly of the third finger. Right foot: the small fourth and fifth digits, without nails, are visible. Profile: note mildly underdeveloped midface, depressed nasal bridge, short and upturned nose, relatively large ears with flat crus superior and inferior, short neck.

Radiographs of the abdomen showed a double bubble, and at surgery, an annular pancreas and intestinal malrotation were corrected. Postoperatively, she became cyanotic, artificial ventilation failed to restore adequate oxygenation, and Extracorporeal Membrane Oxygenation (ECMO) was applied from days 11 to 22. Roentgenograms and CT scan of the thorax showed mild atelectasis of the posterior parts of the lung lobes, and no signs of congenital cystic adenomatoid malformation, embolic obstruction or aberrant pulmonary vasculature. There was pulmonary arterial hypertension with a right-left shunt through the foramen ovale. A lung biopsy showed vascular changes and parenchyma changes (type II hyperplasia and broadened alveolar septa) due to pulmonary hypertension. There were no signs of alveolar capillary dysplasia. Cardiac ultrasonography showed initially thickened asymmetrical aortic valves, but re-evaluation did not confirm this. Ultrasound study of the abdomen showed a horseshoe kidney and dilated ureters, more marked on the right. Ultrasound study of the brain showed a thin corpus callosum, wide peripheral liquor spaces and wide ventricles. Electroencephalography was unremarkable. Ophthalmologic examination showed relatively small corneae (9 mm), and bilateral multiple chorioretinal atrophic lesions, apparent absence of foveal depression, hypopigmentation of fundus, and enlargement of blood vessels. Visually evoked potentials (VEP) and electroretinography (ERG) were not performed. Radiography (Fig. 3) showed 11 pairs of ribs, a smaller right hemithorax, segmentation anomalies of thoracic vertebrae with a hemivertebra at T5, normal clavicles and scapulae, small right ischial ramus and absence of the upper part of the pubic bone on the right. The right humerus and left ulna were bowed, the right ulna and radius were smaller than the left. The right hand showed small fourth and fifth metacarpal bones and phalanges. The right tibia was short and bowed with a small proximal epiphysis.

Figure 3.

Radiographs of pelvis and legs (A), right arm (B), left arm (C), and spine (D) of the present patient. Note the small right ischial ramus, absence of the right upper part of the pubic bone, short and bowed right tibia and small right proximal epiphyses, bowed right humerus and left ulna, small right ulna and radius, small fourth and fifth metacarpal bones and phalanges of the right hand, 11 pairs of ribs, a smaller right hemithorax, segmentation anomalies of thoracic vertebrae with a hemivertebra at T5.

Urinary metabolic screening (including evaluation of oligosaccharides, sialic acid, aminoacids, and mucopolysaccharides) showed an increased excretion of mucopolysaccharides. Unfortunately urinary metabolic screening was not repeated and metabolic screening in plasma was not performed. Additional analysis in cultured skin fibroblasts did not show an aberrant sterol profile and also results of complete peroxisomal analysis in skin fibroblasts were normal. Electronic microscopy studies in skin fibroblasts did not show evidence for storage in fibroblasts or lysosomal changes. Blood karyotype was normal (46,XX). Chromosome analysis of 30 fibroblast metaphase spreads showed no evidence of chromosomal mosaicism, especially no marker iso(12p). A subtelomere MLPA and a 105K whole-genome oligo-array (Agilent) gave normal results. Molecular analysis of SETBP1 known to cause Schinzel–Giedion syndrome [Hoischen et al., 2010] did not show a mutation. Molecular analysis of NSDHL known to cause CHILD syndrome [Bornholdt et al., 2005] gave normal results.

At age 22 days, the child did no longer respond to vasoactive medication, she died at age 26 days. Autopsy was not granted.


The combination of manifestations in the proposita is unusual. Phenotypic analysis showed normal (prenatal) growth but a series of malformations: striking hemi asymmetry; thin corpus callosum without megalencephaly but with wide ventricles and large anterior fontanel; abnormally placed thumbs, hypoplastic thenar eminence and mild radius dysgenesis at the right; annular pancreas; malrotated gut; slightly dorsally placed anus; horseshoe kidney; smaller right hemithorax; vertebral segmentation anomalies with 11 pairs of ribs; hemivertebrae T5; small right ischia ramus and absence of upper part of the pubic bone on the right; short right fourth and fifth metacarpals and phalanges with syndactyly fourth and fifth digits; nail dysgenesis. She showed several deformities: contractures at elbows; bowing of right tibia and ulna; simian palmar crease; clinodactyly third left finger; chorioretinal atrophic lesions. Minor anomalies were high anterior hairline; broad forehead; mildly underdeveloped midface; bitemporal narrowing; hypertelorism; depressed nasal bridge; short upturned nose; large mouth; retrognathia; relatively large ears; short neck; hypertrichosis; enlarged ureters; underdevelopment right labium majus.

We considered first a chromosomal cause, possibly as mosaicism because of the asymmetry of findings, although there were no signs of Blaschko-linear skin pigmentation. Conventional cytogenetics and molecular karyotyping including a whole-genome oligo-array showed no aberrations, and cytogenetic analysis in cultured skin fibroblasts gave normal results as well. This makes a chromosome imbalance less likely although it cannot be excluded completely. If autopsy had been allowed multiple tissues from both body sides could have been analyzed. Striking body asymmetry can also be present in Mendelian syndromes.

Therefore we secondly evaluated the possibility of a metabolic cause. The eye findings and some of the skeletal findings would fit with a sterol or peroxisomal disorder, although no stippling or ichthyosis was observed. Still, some of the findings are reminiscent of CHILD syndrome and related entities [Happle et al., 1980]. Analyses in cultured skin fibroblasts did not show an aberrant sterol profile and a complete check of possible peroxisomal dysfunctions did not show any abnormalities. Molecular analysis of NSDHL known to cause CHILD syndrome gave normal results. General metabolic screening in the proposita showed an increased excretion of mucopolysaccharides, but her clinical phenotype would be extremely unusual for and not compatible with any of the known mucopolysaccharidoses. She had no large spleen or liver. There were also no fractures on radiographs (mucolipidosis). Unfortunately, there has been no opportunity to repeat this investigation to confirm this finding but additional electronic microscopy studies in skin fibroblasts did not show evidence for storage or other lysosomal changes in fibroblasts.

We considered also the possibility of other Mendelian multiple congenital anomaly (MCA) syndromes. The facial appearance, hypertrichosis, large fontanel, enlarged ureters, and the involvement of the skeleton resemble findings in Schinzel–Giedion syndrome (SGS) to some extent (Table I) [Schinzel and Giedion, 1978; Lehman et al., 2008]. SGS is a multiple congenital malformation syndrome characterized by underdeveloped midface, hypertrichosis, multiple skeletal anomalies (asymmetric thorax, small underossified pubic bones, brachymelia), and cardiac and renal malformations. However, the present patient had no signs of epilepsy, hydronephrosis, macroglossia, choanal stenosis, hyperconvex nails, ambiguous genitalia, or ASD, as are characteristics of SGS. Furthermore, molecular analysis of the SETBP1 gene [Hoischen et al., 2010] did not show a mutation. Still, it is uncertain whether SGS is a heterogeneous disorder and we cannot exclude this diagnosis completely.

Table I. Phenotype of the Present Proposita Compared to Major Characteristics of Schinzel–Giedion Syndrome and Urioste Syndrome
 PropositaSchinzel–Giedion syndromeUrioste syndrome
  1. +, Present, −, absent; U, unknown; n.a., not applicable.

 Progressive failure to thriveU+U
 Demise26 daysInfancy/childhoodInfancy
 Developmental delayU+U
 Large ventricles+++
 Underdeveloped callosal body++
 Cortical atrophy++
 Facial hemangioma+
 Large anterior fontanel++
 Prominent forehead+
 Bitemporal narrowing++
 Mid-face retractionMild+
 Prominent eyes+
 Chorioretinal atrophy+
 Deep groove below eyes++
 Low-set, small ears++
 Short upturned nose+++
 Choanal stenosis+
 Short neck+
 Truncus arteriosus+
 Agenesis pulmonary artery/vein+
 Pulmonary hypoplasia/agenesis lung/bronchus++
 Pulmonary hypertension+
Digestive tract
 Esophageal duplication+
 Duodenum atresia+
 Abnormal liverSteatosisHypoplasia
 Annular pancreas++
Urinary tract
 Enlarged ureters++
 Renal/ureteral/bladder agenesis+
 Penisn.a.Small, hypospadiasLarge
 Bicornuate uterus+
 Abnormal labia/scrotum++
 Gap occipital bone+
 Wormian bones+
 Asymmetry thorax+++
 Long clavicles+
 Broad ribs+
 Spinal segmentation anomalies++
 Small/underossified pubic bones+++
 Small iliac wings
 Absence radius/ulna/digiti+
 Broad metaphyses+
 Small distal phalanges++
 Short first metacarpal+

The segmentation defects of the vertebrae, asymmetrical limb deformities and congenital defects of several internal organs in our patient also showed overlap with Urioste syndrome (Table I) [Urioste et al., 1996; Martínez-Frías et al., 1997]. However, our patient lacked the severe limb hypoplasia with the appearance of phocomelia, polydactyly of feet, supernumerary ribs, and the facial phenotype in our patient is different. Until now no cause for Urioste syndrome is known.

Other diagnoses considered and judged to be unlikely are a case report on a single patient with infantile spasms, retinal lesions, facial and limb anomalies [Plomp et al., 2000], a mutation in FLNA [Robertson 2006], Coffin–Siris syndrome [Coffin and Siris, 1970], acrofacial dysostosis [Hennekam et al., 2010], and CHARGE syndrome [Pagon et al., 1981].

In summary, we describe here a female patient with a unique multiple congenital anomalies (MCA) syndrome and a distinct phenotype. We have been unable to find a description of a patient with a similar constellation of morphologic features and congenital anomalies. The resemblance with the previous mentioned syndromes seems not sufficient in any of these to explain the phenotype of this girl completely, and possibly this combination of findings represents a hitherto unreported entity. The etiology remains uncertain: there is no clue for a teratogenic cause, a chromosomal imbalance has been made unlikely as far as possible and a metabolic cause appears unlikely as well. Consanguinity is not present, and family history is unremarkable for similar or likely related anomalies. Further reports of similar patients may provide an answer.


We thank the parents of our patient for their help, the Cytogenetic Laboratory of the Department of Human and Clinical Genetics Leiden and Rotterdam for cytogenetic analysis, MLPA, and whole-genome oligo-array (Annelies de Klein), Department of Human Genetics, RUNMC, Nijmegen for molecular analysis of the SETBP1, Marja Wessels, Alice Brooks, Grazia Mancini, Robert Jan Houmes (Rotterdam) for their suggestions, and Arie van Haeringen (Leiden) and Fleur van Dijk (Amsterdam) for their help in obtaining documentation of earlier hospitalization.