Answer

We present a case of Aarskog-Scott Syndrome.

Prenatal ultrasound demonstrated the following findings:

• Flattened facial profile due to maxillary hypoplasia and a short nose with a broad nasal bridge
• Hypertelorism
• Mild brachydactyly of both hands
• Broad feet and hands
• Brachycephaly
• Single umbilical artery
• Mild polyhydramnios (AFI = 22.9 cm, MVP = 7.2 cm)
• Short humerus

Cardiac anatomy and neurosonography appeared normal. Genetic testing, including amniocentesis with chromosomal microarray and whole exome sequencing, was recommended, but declined by the patient. Postnatal whole exome sequencing was performed and revealed a pathogenic mutation in FGD1, confirming the diagnosis.

Discussion

Aarskog-Scott syndrome (OMIM #305400), also known as facio-digito-genital syndrome, is a rare developmental disorder primarily affecting males and characterized by distinct craniofacial, skeletal, and genital abnormalities [1]. In 1970, Dagfinn Aarskog, a Norwegian pediatrician and geneticist, described seven males in three generations of a family with a syndrome of short stature, round facies, hypertelorism, short nose with anteverted nostrils, broad upper lip with marked philtrum, inguinal hernia, undescended testes, and a scrotal skin fold extending ventrally around the base of the penis. All the affected subjects had normal motor and mental development [2]. A year later, Charles Scott, Jr, an American geneticist, reported three brothers with similar characteristics and some additional findings (small hands with short fingers and joint hypermobility) which completed the definition of the entity [3].

The exact incidence of this pathology is unknown due to its wide clinical variability and mild physical signs. The population prevalence is estimated to be approximately 1 in 25,000 [4]. Although sex-influenced autosomal dominant and recessive inheritance patterns have been described [5,6], only an X-linked recessive form associated with mutations in the FGD1 gene is recognized as the cause of this syndrome [7,8]. To date, 147 variants have been published (https://databases.lovd.nl/shared/genes/FGD1) including missense, nonsense, deletions, insertions and gross rearrangements [4]. The FGD1 gene (formerly named FDG1, changed to conform with standardized genetic nomenclature in early 2000's), located on the Xp11.22 region of the X chromosome, encodes a guanine nucleotide exchange factor (GEF) that activates Cdc42, which participates directly in cytoskeletal organization, growth regulation, and normal embryonic development in all mammals [9]. The clinical phenotype does not seem to correlate with the type and position of the mutation [10].

Aarskog-Scott syndrome is recognized as a pleiotropic disorder (multiple and distinct phenotypic traits caused by a single gene) involving the skeletal system, face, and external genitalia, with highly variable expressivity even within the same family [11,12]. The most characteristic findings are proportionate short stature, short limbs (usually rhizomelic), broad hands and feet, genital anomalies (shawl scrotum), and facial dysmorphism. The name facio-digito-genital dysplasia is justified in view of the high prevalence rates of hypertelorism (94.8%), brachydactyly (62.1%), and shawl scrotum (79.3%) [10]. Organizing clinical findings according to their prevalence is useful for management of patients with rare genetic diseases, facilitating the selection of genetic tests that provide a definitive diagnosis. Teebi et al [13] reviewed more than 130 males with Aarskog-Scott syndrome published up to 1993 and divided their findings into primary and secondary diagnostic criteria according to their frequency. Primary manifestations, which are present in more than 80% of reported patients, include short stature, hypertelorism, short nose with anteverted nares, maxillary hypoplasia, a crease below the lower lip, mild interdigital webbing with short and broad hands, short fifth finger with clinodactyly, and shawl scrotum. Secondary criteria are less frequent, present in 50 to 70% of the patients, and include abnormal auricles with fleshy lobules, posteriorly angulated ears, widow’s peak, ptosis, downward slant of palpebral fissures, joint hyperextensibility, broad feet with bulbous toes, cryptorchidism, inguinal hernia, and prominent umbilicus. More recently, Zanetti et al. classified the findings into primary (prevalence ≥ 50%), secondary (between 30% and 49%), and additional (between 15% and 29%) criteria [10]. Mental retardation and/or attention deficit/hyperactivity disorder may be part of the Aarskog-Scott syndrome phenotype [14,15]. Patients with mental impairment are only mildly affected, with learning and behavioral disabilities often confined to early childhood [16]. Facial features and the typical morphology of the hands change with age (hypertelorism less evident, forehead less prominent, and face more elongated), making clinical diagnosis difficult in adults.

Affected males inherit the pathogenic variant from their carrier mothers. Each son of a carrier woman has a 50% chance of being affected and each daughter has a 50% chance of being a carrier.  Female carriers may present a milder phenotype than males, possibly due to the X-chromosome inactivation pattern, showing minor dysmorphic features such as short stature, hypertelorism, round face and characteristic hands and feet, with abnormal migration of the labioscrotal folds having been described in a girl from a family with Aarskog-Scott syndrome [11,17].

Prenatal diagnosis of Aarskog-Scott syndrome is rare. To the best of our knowledge, only four cases are documented in the literature, identified in high-risk pregnancies [12,18,19]. Although it is often diagnosed only postnatally based on characteristic physical features and developmental history, certain distinct but subtle ultrasound signs may raise prenatal suspicion, especially in the second or early third trimester. In our case, retrospective review of the prenatal ultrasound images and video clips, following genetic confirmation, allowed us to better appreciate subtle and previously overlooked features consistent with the phenotype commonly described in Aarskog-Scott syndrome:

1. Craniofacial Anomalies:

• Hypertelorism – a consistent and sometimes striking feature. It may be detectable by measuring interorbital distance or binocular diameter.
• Short and broad nasal bridge, small and short nose with anteverted nostrils and short maxillae, leading to flattened midface also called midfacial hypoplasia ("Binder-like" profile).
• Large earlobes, often low-set
• Mild brachycephaly – occasionally present and observable as a shortened occipitofrontal diameter with a relatively preserved biparietal diameter.

2. Skeletal Findings:

• Mild shortening of long bones, especially the humerus and femur, though still within the borderline normal range. These features may mimic constitutional growth delay but should be considered suspicious in the proper context.
• Broad hands with brachydactyly, often subtle and difficult to appreciate
• Broad feet or broad first toes – best seen in plantar views.

3. Genital Features:

• Shawl scrotum, manifestation of a penoscrotal transposition with the skin of the scrotum surrounding the phallus frontally, is a highly suggestive finding, although not assessable prenatally.
• Cryptorchidism – undescended testes may be suspected with careful examination of the scrotal sac, although only in the late third trimester, confirmation often awaits postnatal physical examination.

While none of these features are pathognomonic on their own, their combination can be specific for Aarskog-Scott syndrome and should prompt further genetic evaluation. Intrauterine growth retardation and shortening of the long bones are among the most typical prenatal findings of this condition, but this feature is particularly nonspecific [1,20]. Umbilical anomalies, including single umbilical artery, flat configuration of the umbilicus, and protruding umbilicus are not considered specific, but have been reported in association with Aarskog-Scott syndrome. [12, 21]

Congenital malformations have been described in patients with Aarskog-Scott syndrome, such as congenital heart defects (septal defects, aortic root dilatation), thickened corpus callosum, gyration abnormalities, cerebrovascular dysplasia, inguinal hernia, cleft lip and palate, cervical spine abnormalities (spina bifida occulta, fused cervical vertebrae), dolichomegasigmoid, and anal anomalies [1,19,22-25]. Additional clinical studies are needed to determine whether these malformations are a coincidence or rare manifestations of Aarskog syndrome.

In the presence of findings suggestive of Aarskog-Scott syndrome, the recommended genetic diagnostic flow includes targeted single-gene sequencing of the FGD1 gene, multi-gene panels for syndromic short stature or facial dysmorphism, chromosomal microarray (CMA), and whole exome sequencing (WES) in cases with negative CMA. Carrier testing in mothers of affected male fetuses is crucial to confirm inheritance pattern and assess recurrence risk.

The differential diagnosis includes Noonan syndrome, Robinow syndrome, and SHORT (Short stature, Hyperextensibility of joints, Ocular depression, Rieger anomaly and Teething delay) syndrome [4,10,18]. Noonan syndrome shows significant clinical overlap with short stature, hypertelorism, genital anomalies, and ptosis. Robinow syndrome also has many clinical similarities (short stature, hypertelorism, facial features), but these individuals never present a shawl scrotum.

References

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Discussion Board

Winners

Javier Cortejoso Spain Physician

Ionut Valcea Romania Physician

Le Tien Dung Viet Nam Physician

ASHLEA HARDIN United States Sonographer

ANDRES ARENCIBIA MOLINA United States Physician