Paula and Bobby
Parents of Lillie
What is Robinow syndrome?
Robinow syndrome is a rare genetic condition that was first identified in 1969.
The disease has two forms, autosomal dominant and autosomal recessive, and depending on the type causes varying severity of symptoms.
The defining features of the syndrome include short-limbed dwarfism, anomalies affecting the head and face, as well as anomalies affecting the external genitalia of a diagnosed individual.
What gene changes cause Robinow syndrome?
The autosomal recessive form of the syndrome is caused by mutations in the ROR2 gene. Symptoms associated with this type of the syndrome are generally more severe.
Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.
The autosomal dominant form of the syndrome is caused by mutations to the WNT5A or DVL1 genes. Symptoms are generally milder with this type of the syndrome.
In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
What are the main symptoms of Robinow syndrome?
Facial and physical characteristics include short limbs and dwarfism. Short fingers and toes as well as small hands. A cleft tongue, depressed nose bridge, eye folds, a downward pointing mouth, low set ears, a short neck and thin upper lip.
Individuals with the syndrome may also experience fused or missing ribs, underdeveloped genitalia, dental problems and kidney and heart defects.
How does someone get tested for Robinow syndrome?
The initial testing for Robinow syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical Information on Robinow Syndrome
The most common skeletal features of Robinow syndrome are mesomelic short stature and facial dysmorphism, but the presentation is variable and can also include abnormalities in the genitalia, heart, teeth and kidneys. Robinow syndrome, autosomal dominant 1 is caused by mutations in the WNT5A gene.
This syndrome was first described by Robinow et al., (1969). Clinical characteristics included mesomelic limb shortening, short stature, flat facial profile, prominent forehead and hypertelorism. Other features include a micropenis in males, hydronephrosis or urinary tract infections, cleft lip and palate, and hemivertebrae.
The facial features are said to resemble those of a fetus, with a prominent forehead, hypertelorism, a wide mouth and a small nose with anteverted nostrils. There may be significant gum hypertrophy.
Mesomelic limb shortening is usually (but not always) apparent. Note that stature can sometimes be normal (see Bain et al., 1986 and Saraiva et al., 1999).
Schonau et al., (1990) reported a male infant who presented with ambiguous genitalia and persistence of the Mullerian ducts. Histology of the testes was normal whereas endocrinological studies showed partial deficiency of androgen receptors.
Balci et al., (1993) reported 14 cases from Turkey. Many of these cases had a split hand appearance, and one had an extra hypoplastic mesoaxial digit. Because of the high incidence of consanguinity, it is possible this series represents the recessive form of the condition.
Samoud et al., (1993) reported a case with sensorineural deafness.
The condition may be particularly frequent in Turkey (Aksit et al., 1997). The authors reported a case with almost complete syndactyly of the toes.
Balci et al., (1998) reported a further case from Turkey with vaginal atresia, hematocolpos and an extra middle finger.
Atalay et al., (1993) and Al-Ata et al., (1998) reported cases with tricuspid atresia and reviewed the evidence for congenital heart disease in this condition. They found that eight out of 53 cases had congenital heart defects. The lesions included ASD, Fallot tetralogy, coarctation of the aorta, valvular and peripheral pulmonary stenosis, VSD, and PDA.
Robinow (1993) provides a good review. Patton and Afzal (2002) provide a good review of the clinical and genetic aspects.
A midline cleft of the lower lip was reported by Kargi et al., (2004).
Tufan et al., (2005) reported two unrelated adults with a molecularly proven recessive form who had endocrine anomalies in one (low testosterone levels) and a rudimentary kidney with renal insufficiency in the other.
Autosomal dominant and recessive families have been reported. Bain et al., (1986) reviewed the literature and noted that the definite recessive cases had significant vertebral anomalies and more severe mesomelic shortening of the arms, with abnormally modelled radii and ulnae.
However, this distinction may not be absolute. Mazzeu et al., (2007) also looked at AD and AR families (AR families were designated as such if the family history was compatible or if rib fusion was present). Hemivertebrae and scoliosis were much more common in AR cases, and umbilical hernia and supernumerary teeth were exclusively found in AR cases.
Mazzeu et al., (2007) reviewed clinical characteristics of 88 patients, including 37 with recessive type and 51 with dominant type. The most frequent clinical characteristics included (dominant versus recessive, respectively): anteverted nares (95.5% vs 96.2%), brachydactyly (81% vs 91.4%), clinodactyly (70% vs 87.8%), dental malocclusion (49.4% vs 93.6%), depressed nasal bridge ( 77.9% vs 48.7%), down-slanted mouth corners (62.9% vs 95.2%), hemivertebrae (22.7% vs 97.5%), hypertelorism (100% both), hypoplastic clitoris (45.9% vs 79.4%), hypoplastic labia minora (50.4% vs 80.8%), mesomelic limb shortening (80.1% versus 100%), micropenis (84.1% vs 100%), midface hypoplasia (80.6% vs 94.2%), prominent forehead (79.0% vs 77.8%), scoliosis (17.6% vs 77.4%), short hands (61.5% vs 83.9%), short nose (81.2% vs 93.2%), short stature (81.2% vs 97.3%), triangular mouth (64.9% vs 86.2%), upturned nose (86.7% vs 97%) and wide nasal bridge (96.8% vs 96.8%).
Person et al., (2010) reviewed the original family described by Robinow in 1969 and identified heterozygous missense mutations in the WNT5A gene.
Three de novo mutations in the WNT5A gene were reported by Roifman et al., (2015). The cases had a classical dominant Robinow phenotype.
Xiong et al., (2016) describe a Chinese girl with a de novo c.249C>G (p.Cys83Trp) variant in the WNT5A gene with classic features but normal stature.
* This information is courtesy of the L M D.
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