Genetics

The severity of signs and symptoms and the pattern of heritability distinguish the types of Robinow syndrome. Biallelic variants in the ROR2 and the Nucleoredoxin (NXN) genes have been implicated in the recessive forms of the syndrome. ROR2 protein is essential in embryonic development, contributing to the early formation of chondrocytes and the development of cartilage and growth plates; also, it has been reported to be necessary for normal skeletal, heart, and genitalia formation. Patients with the NXN variant have milder skeletal anomalies than those with the ROR2 variant. Dominant forms of the syndrome have been associated with multiple genes, including variants and deletions of WNT5A on chromosome 3p14.3, as in the present case; however, we identified a new mutation (Figure 2). Other variants described include the DVL1 gene, variants in DVL3, and frizzled class receptor 2 (FZD2). Recently, variants have been described in glypican 4 (GPC4), suggesting a form of X-linked Robinow syndrome³,⁵,⁷,⁸.

Phenotype

The phenotypic presentation of the syndrome is variable. Certain features have been observed to be more prevalent in some genetic variants. However, they have yet to be reported as variant-specific because of discrepancies due to small study populations and global incidence of the syndrome¹. The autosomal dominant variant (ADRS) is rare and has been reported with milder craniofacial and musculoskeletal anomalies than the ROR2 variant. The musculoskeletal system is minimally affected, with the possibility of the patient having average stature with little or no limb shortening³,⁷,⁸.

Conversely, the autosomal recessive variant (ARRS), especially with ROR2 gene mutations on chromosome 9q22, presents dysmorphism, multiple facial anomalies, limb, and thoracic malformations, rib and vertebral abnormalities, mesomelic short stature and genital malformations².

Craniofacial alterations. The most frequent malformations are macrocephaly, broad and prominent forehead, low ear implantation, ocular hypertelorism, prominent eyes with deficient lower eyelid, midfacial hypoplasia, short upturned nose with depressed nasal bridge and anteverted nares, large triangular mouth with tent-like upper lip, long philtrum, gingival hypertrophy, misaligned teeth, ankyloglossia, bifid tongue, and micrognathia. Other less frequent findings are cleft lip and palate. Asymmetric exophthalmos was found only in patients with DVL1 and NXN variants, while a saddle nose deformity in DVL1, ROR2, and NXN variants. Typical craniofacial anomalies were observed in this patient (Figure 3A), macrocephaly, low ear implantation, ocular hypertelorism, prominent eyes with deficient lower eyelids, depressed nasal bridge, long philtrum, tent mouth, and micrognathia³,⁴,⁹.

Figure 3 A: frontal and lateral phenotypic features of Robinow syndrome. Macrocephaly, low ear implantation, ocular hypertelorism, prominent eyes with deficient lower eyelids, long philtrum, and tent mouth (left panel). Low ear implantation, depressed nasal bridge, and micrognathia (right panel). B: patient at age 10 years. Mesomelic limb shortening (left panel). Low ear implantation, depressed nasal bridge, and micrognathia (upper right panel). Low ear implantation and ocular hypertelorism (lower right panel). 

Musculoskeletal alterations. Abu-Ghname et al. found that 100% of the patients had short-limb skeletal dysplasia and, in most cases, mesomelia, followed by micromelia and rhizomelia⁷. Patients with ROR2 and GPC4 variants had exclusively mesomelic skeletal dysplasia, not found in the NXN variant. Other limb anomalies documented were the radial arch and radial head dislocation and diminished arm rotation. The most prevalent hand anomalies were brachydactyly, clinodactyly, and broad thumb. Genu valgum was a common finding in the lower extremities. Spinal anomalies were directly related to the type of variant: on the one hand, single butterfly vertebra with the autosomal dominant variant; on the other hand, hemivertebra, vertebral fusion, and narrow interpedicular space with the autosomal recessive variant. However, this patient presented only one musculoskeletal anomaly: short limb skeletal dysplasia (Figure 3B). No other anomalies were reported at this level¹,²,⁴,¹⁰.

Genital alterations. The most frequently observed anomaly is micropenis, as in the present case. Other anomalies found are penile transposition, cryptorchidism, testicular atrophy, hypospadias, and an elongated penopubic gap in males. In females, the reduced size of the clitoris and hypoplasia of the labia majora predominate. In 1997, Wilcox et al. described the possible etiology of micropenis as secondary to inferior-posterior insertion of the penis on the medial part of the ischial tuberosity, as its normal insertion is on the anteromedial portion of the pubis. Therefore, the penis is buried in the scrotum, resulting in a short appearance of a normal-sized penis. Consequently, many patients should not be classified with a micropenis (stretched penis length < 2.5 SD below the average penis length for age)⁸,⁹,¹¹.

Urinary system alterations. Although the most prevalent finding is hydronephrosis, cystic dysplasia of the kidney and renal duplication have also been described. Cases of renal failure of unknown origin have also been reported, but this has not been directly related to Robinow syndrome. This anomaly was not observed in this patient⁸,⁹.

Cardiac and pulmonary alterations. Defects at these levels are frequent, causing premature death in childhood and adolescence in 5-10% of patients. Cardiac anomalies are present in approximately 15% of published cases (< 25% of patients with ADRS). The most often reported is pulmonary valve stenosis or atresia. Atrial septal defect, VSD, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia have also been described. Our patient presented with a systolic murmur at birth, showing VSD, PDA, and pulmonary valve insufficiency. He was treated with surgical correction of these anomalies, and an epicardial pacemaker was placed. He is currently awaiting a new valve replacement; he has no cardiac decompensation and is being treated with diuretics⁴,⁸,¹⁰,¹².

In most cases, no deficit in intellectual functions has been found. However, mental retardation and developmental delay have been observed in up to 20% and 10-15% of the disease carriers, respectively. A frequent finding is the presence of an empty sella turcica. However, it does not seem to be related to GH deficiencies or to predispose to a negative response to hormonal treatment. Developmental brain dysplasia and communicating hydrocephalus have been reported in very few cases, but no distinction has been made between dominant and recessive variants. Hearing loss has also been described in some cases due to cranial osteosclerosis. This patient has no neurological defects, has developed adequately, and attends school with no apparent impairment⁴,⁸,¹⁰,¹²-¹⁴.

Endocrinology

The characteristic findings in this syndrome are short stature and slow growth velocity (GV). Soliman et al. observed short stature at birth, with a length of 41.1 ± 2.1 cm (-3.7 ± 0.35 SD) and slow GV during the first year of life (13.1 ± 3.1 cm per year). At the end of the first year, the mean height was 57.4 ± 4.9 cm (-5.8 ± 0.9 SD), reflecting a low growth potential¹⁴.

In several studies, overall growth was found to be -2.17 SD below the mean. It persists into adulthood but is usually not severe, with a mean final height of –2 SD. Adult height has been reported to range from 161.7 to 170 cm¹⁴.

Children with Robinow syndrome display growth hormone deficiency, although normal insulin-like growth factor-1 (IGF-1) concentrations have been described. This patient's low growth deficiency was corroborated with a growth hormone challenge test. Thyroid function tests and morning cortisol concentrations are usually not affected in these patients¹⁴.

Diagnosis

Diagnosis is based on clinical suspicion due to craniofacial, musculoskeletal, and genital characteristics of the syndrome. Imaging tests are needed to observe bone anomalies in the extremities, skull, and spine. Subsequently, a genetic panel should be performed to confirm the diagnosis, consisting of DVL1, DVL3, FZD2, NXN, ROR2, WNT5A, and GPC4³. It is essential to detect congenital heart defects at birth, as these are the leading cause of mortality in the first year of life⁴.

In cases with genetic risk, prenatal diagnosis can be performed from 19 weeks of gestation by ultrasound to determine the length of different bone components⁸.

Differential diagnosis

Aarskog syndrome and achondroplasia should be considered possible differential diagnoses when Robinow syndrome is suspected.

Aarskog syndrome is an X-linked genetic syndrome caused by an FGD1 mutation. This syndrome is characterized by short stature, short hands and feet, craniofacial dysmorphism, genital anomalies, and intellectual disability¹⁰,¹²,¹⁵,¹⁶.

Achondroplasia is an autosomal dominant genetic syndrome caused by an FGFR3 mutation. This syndrome is characterized by short rhizomelic stature, hyperlordosis, brachydactyly, macrocephaly with frontal prominence, and midface hypoplasia¹⁰,¹²,¹⁵,¹⁶.

Treatment

There is no cure for Robinow syndrome. Treatment focuses on decreasing clinical manifestations and reducing complications. Musculoskeletal symptoms may improve with physical therapy or prosthesis placement; if these fail, treatment would be surgical. Cardiac anomalies require surgical correction and, in some cases, long-term pharmacological treatment².

Surgical treatment is performed to correct certain anomalies, such as syndactyly, severe scoliosis secondary to hemi-vertebral or costal anomalies, cleft lip or cleft palate, and anomalous penile insertion⁹.

Hormonal therapy with human chorionic gonadotrophin and testosterone has improved penile length and testicular volume. This patient was treated with testosterone from the age of 4 years due to micropenis. He responded well to treatment with increased penile length and started puberty at 12.5 years⁴,⁹.

An increase in GV has been described following recombinant growth hormone (rhGH) administration; however, an increase in bone age occurs. Consequently, Kawai et al. concluded that rhGH therapy accelerates bone age without significantly increasing final height. Luteinizing hormone supplementation has been reported to improve final height in patients with precocious puberty. We observed an increase in our patient's growth rate, improving his adult height prediction. He started growth hormone replacement at 4 years and consistently improved, reaching the 44^th percentile in height (Figure 4). To date, his height is 155.6 cm (-0.14 SDS)²,⁶,⁹,¹²,¹⁷. The patient's last bone age reported was 13.16 (Greulich & Pyle), with a chronological age of 12.6 years.

Figure 4 Height-for-age and weight-for-age percentiles (2 to 20 years). 

Surveillance

Head circumference should be measured regularly during infancy and childhood. Development assessment should be performed periodically every three months in infants and then every six months to one year. More frequent examinations may be performed if necessary due to identified cognitive delays¹⁰.

Dental evaluation is recommended every six to twelve months or as needed. During childhood, a periodic hearing evaluation is also recommended. If cardiac or renal abnormalities are detected, an assessment of these is also required. The patient is currently undergoing treatment with an orthodontist as he needed treatment for micrognathia: mandibular advancement with an intraoral device¹⁰.

Prognosis

The prognosis is usually good; more than 80% of patients have normal intellectual functions. The severity of the syndrome will depend on cardiac, pulmonary, and renal complications⁸,¹².