Aarskog-Scott syndrome: clinical and molecular characterisation of a family with the coexistence of a novel FGD1 mutation and 16p13.11-p12.3 microduplication

Abstract

Aarskog-Scott syndrome (AAS), also known as facio-genital dysplasia or faciodigitogenital syndrome, is a rare genetic disorder clinically characterised by facial, limb and genitalanomalies. Although also autosomal dominance and recessive patterns have been reported, up to now, only an X linked form associated to mutations of the FGD1 gene has been recognised as causative for this syndrome.

In this case report, we describe a large Italian family in which three members across three generations show classical features of the syndrome. The youngest patient, the proband, and his mother were both molecularly studied and characterised for the not previously reported variant c.1828C>T (p. Arg610*) in the FGD1 gene but with the classic phenotype of AAS. Additionally, both the proband and his mother present a 2.5 Mb 16p13.11-p12.3 microduplication, a genetic variant still unclear for the phenotypic consequences: the co-occurrence of the two rare conditions is discussed for the possible clinical significance.

Background

In this study, we discuss the recurrence of the two rare associated genetic conditions, whose possible clinical and phenotypic significance are not yet clear.^{1 2}

The peculiarity of the work lies in the description of an entire Italian family in which three members of three generations show the classic dysmorphic features of the syndrome and the consistent behavioural manifestations for FGD1 mutations.³

On the other hand, detection of a16p13.11 microduplication remains random and without clinical significance.

Case presentation

The proband was first referred to the Clinical Unit at the age of 16 months for a diagnostic workup of his short stature and atypical facial features. The boy is the second child of healthy, non-consanguineous Italian parents. He had eight siblings, two sisters and six brothers, two of whom show clinical features of Aarskog-Scott syndrome (AAS) (figure 1, given by the family); as referred by the proband’s parents, these two siblings have had a normal life and reached an adult stature of 150 and 152 cm, respectively (figure 2).

Figure 1.

Affected members of the first generation.

Figure 2.

Genealogic tree of the family.

The patient was born at the 38th week of gestation after a scheduled caesarean section. He had a birth weight of 2930 g, a birth length of 48 cm and a head circumference of 36 cm. Apgar Scores were 7 and 10 at 1 and 5 min, respectively. At birth, the hands were flexed, and congenital talipes equinovarus and ectopic testis were present. Treatment for talipes equinovarus was performed by the Ponseti method with good results, and at the age of 9 months, the ectopic testis was surgically corrected. All development milestones were reached within a normal range, but growth (ie, weight and length) was poor.

At the first admission, the patient showed fairly good conditions, with normal social interaction. At 16 months, his weight was 8.5 kg (3rd percentile), height was 72 cm (<3 SDs) and head circumference was 49 cm (75th percentile). At 20 months, the patient was 8.6 kg (<3 SDs), 75 cm tall (<3 SDS) and with a head circumference of 49 cm (50th–75th percentile). At 23 months, his weight was 8.8 kg (<3 SDs), height 80 cm (3rd percentile) and head circumference 49.5 cm (50th percentile). At 31 months, his weight was 9 kg (<3 SDs), height 88 cm (25th percentile) and head circumference 50 cm (50th–75th percentile) (figures 3 and 4).

Figure 3.

The patient’s clinical features. Of note: short nose, broad nasal bridge and furrow in the ear lobes.

Figure 4.

Growth chart of the proband.

The craniofacial anomalies were various and appreciable but not defacing and consisted of thin hair, widow’s peak, rounded face, high forehead, con’s lick, chubby cheeks, telecanthus, hypertelorism, ptosis (prevalent in the right eye), downward slanting palpebral fissures, short nose with anteverted nostrils, broad nasal bridge, wide long philtrum, normal palate and small teeth, small mouth with thin lips, underdeveloped maxilla, crease below the lower lip and a low jaw (figure 3). The ears were low set, with a bifid right lobe and a thick left lobe. The hands were short, broad and flexible (figure 5); the fifth finger was short and demonstrated clinodactyly, there was partial syndactyly of the second, third and fourth fingers, and all fingers showed interphalangeal joint contractures, bilateral simian creases, with dyschromic and hypoplastic nails. The feet were short and broad, with enlarged toes. Pectus excavatum was present. Examination of the genital organs revealed that cryptorchidism had been corrected; inguinal hernia and shawl scrotum were noticed (figure 6).

Figure 5.

The patient’s hand at 20 months. Note the low implant of the thumb, short and flexed fingers (in particular the fifth finger, which also shows clinodactyly).

Figure 6.

Patient’s genitals at 20 months. Note the small genitalia and shawl scrotum.

During several admissions to the hospital, the patient was submitted to laboratory investigations. Routine analysis including blood count, coagulation tests, blood lactate, pyruvate, glucose and ketones, creatine phosphokinases, copper, ceruloplasmin, plasmatic and urinary amino acids, urinary organic acids, purine and pyrimidine, thyroid tests, insuline-like growth factor (IGF1); all tests were normal. ECG and echocardiography were normal, as well as Cox’s femoral and abdominal ultrasounds. Skeletal X-ray showed a hand with short and broad metacarpal nuclei, mild dysmorphism, with the pointed aspect of the distal phalanges. The ossification of the nuclei of the carpus was regular.

Brain MRI was normal, as well as awake and asleep Electroencephalography (EEG) (sleep deprived). No neurological signs were present. A neuropsychiatric evaluation performed at 6 months and 2 years of age showed mild motor and language delay, with Griffith Mental Developmental Scale Scores of 62.6 (locomotor 82.6, personal–social 58.7, hearing and language 28.3, hand–eye coordination 58.7, performance 84.8 and practice reasoning 62).

An FGD1 gene screening for mutations showed the presence of the variant c.1828C>T, in the exon 10 (RefSeq: NM_004463.2), predicted to result in premature protein termination (p. Arg610*), while a Array - Comparative Genomic Hybridization (CGH-array) documented a 16p13.11-p12.3 microduplication of 2.5 Mb: both the genetic variations were of maternal origin.

Investigations

During several hospital admissions, the patient underwent routine laboratory investigations, which were found to be all normal.⁴

The first basic clinical data were provided, thanks to skeletal radiography showing a hand with short and wide metacarpal nuclei, slight dysmorphism, with the pointed aspect of the distal phalanges.⁵

Furthermore, thanks to the associated neurobehavioural disorders they have been demonstrated thanks to a neuropsychiatric evaluation with a slight motor and language delay.⁶

Finally, through the screening of the FGD1 gene for mutations, the presence of the variant c.1828C>T and a CGH-array have been documented, a 16p13.11-p12.3 microduplication of 2.5 Mb: both genetic variations of fundamental importance for etiopathological diagnosis.

We proceeded to demonstrate through precise images how the anomalies inherited in the family being X linked. The typical phenotypic characters were already present in the predecessors.

Differential diagnosis

The correct genetic identification of syndromic pathologies subordinated by the heterogeneous and variable phenotypic expression of the different known pathogenic mutations. In particular, depending on the genetic modifiers, patients can present profound differences in the expression of the typical AAS phenotype deriving from the FGD1 mutation, as discussed by Quintela et al⁶, following the mechanism previously hypothesised for coexistence with the SOX5 gene, or another gene involved in the development processes.^{6 7}

Treatment

Supportive therapy is necessary if the 16p13.11 microduplication itself involves in a certain clinical relevance, since the carriers can be normal or, on the contrary, they can show a wide range of anomalies, most commonly behavioural disturbances or language delays that reduce their autonomy.⁸ Hormone replacement therapy was not administered in our case reported due to the normal test values obtained. Subsequent endocrinological consultation did not reveal any signs of related pathology; therefore, a subsequent re-evaluation after 6 years of the patient was recommended.

Outcome and follow-up

In the family we report, the detection of a 16p13.11 microduplication did not, today, result in any deviation from the classic clinical phenotype

Every 6 months, serological follow-ups from neurological, cardiological, neuropsychiatric as well as endocrinological and metabolic and ENT operations are performed for associated craniofacial malformations, language and hearing disturbance.

No organic disturbances of the nervous system or of the cardiovascular system have yet been found.

The last brain MRI performed was normal, as was the EEG performed during monitoring. The neuropsychiatric evaluation performed at 6 months and 2 years showed a slight motor and speech delay, with the evaluation of the Griffith Mental Development Scale of 62.6 (locomotive 82.6, 58.7, personal–social, hearing and speech 28, 3, hand–eye coordination 58.7, performance 84.8 and practical reasoning 62).

The auxological state-weight control at 20 months, the patient was 8.6 kg (<3 SD), 75 cm tall (<3 SD) and with a head circumference of 49 cm (50th–75th percentile). At 23 months, her weight was 8.8 kg (<3 SD), height 80 cm (3rd percentile) and head circumference 49.5 cm (50th percentile). At 31 months, her weight was 9 kg (<3 SD), height 88 cm (25th percentile) and head circumference 50 cm (50th–75th percentile) (figure 4).

The patient to date has unchanged the aforementioned craniofacial anomalies thin hair, widow's tip, rounded face, high forehead, plump cheeks, telecanthus, hypertelorism, ptosis (prevalent in the right eye), eyelid fissures inclined downwards, short nose with ante-inverted nostrils, wide nasal bridge, wide long filter, normal palate and small teeth, small mouth with thin lips, underdeveloped jaw, fold under the lower lip and lower jaw (figure 3).

In order to adequately monitor psychophysical development and auditory maturation and language acquisition, serial checks must be performed every 6 months in the absence of relevant organic or functional anomalies, while follow-up must be restricted if there are debilitating or potentially harmful conditions the overall development of the patient.

DISCUSSION

The clinical features in the affected members of this family were typical of AAS.⁹

The proband showed, as one of the main features, a disproportionate short stature with increased upper to lower segmental ratio. Height was initially noticeably below the 3rd percentile but has shown a partial, progressive retrieve. Growth curves in the proband were irregular: at birth, the patient’s weight, height and head circumference were all within the normal ranges. The growth in height and weight began to fail in the first months of life and persisted slow till the actual age. However, height showed progressive improvements, reaching the 25th percentile at 31 months. The patient’s height might be positively influenced by paternal height (ie, 180 cm). A very low stature at adult age was showed also for the two clinically affected members of the first generation (subjects II-7 and II-8 in the pedigree), although they lived a normal life with good intellective capabilities and without impaired fertility (figure 1).

The head circumference of our patient appeared disproportionate relative to height although within the normal range for his age (between the 50th and 75th percentile). The facial features were similar to those found in other reported cases. The main clinical features of AAS were reported by Porteous and Goudie,¹⁰ including the furrow in the right lobe (which is not commonly reported).¹⁰

Disorders in cognitive abilities and behaviour have been variously reported in AAS.^9–12 A review by Berman et al found that individuals affected by AAS do not experience cognitive delays (38 out of 43 published patients presented with average intelligence).⁹ An IQ study was conducted by Logie and Porteous¹¹ in 21 boys affected by AAS, using the Griffiths Mental Developmental Scale and the British Ability Scale.¹¹ In that study, patient IQ ranged from 68 to 128 and showed a normal distribution, demonstrating the absence of cognitive involvement in most of these patients. In general, in the cases reported in the literature, with the exception of a case of X linked mental retardation associated to the p.Pro312Leu mutation of FGD1, FGD1 mutations are not associated with severe mental retardation and AAS individuals seem to show, at most, a mild cognitive impairment, with learning and behavioural disabilities often confined to early childhood, with a good evolution of mental status into adulthood.^{13 14}

Accordingly, in our patient, only mild motor and language delays were reported with good social contact and cognitive performance.

At present, FGD1 is the only gene known to cause AAS and a number of causative mutations have been reported.¹⁵ In our patient, molecular analysis of the FGD1 showed the presence of the novel mutation c.1828C>T, which introduces an early termination codon (p. Arg610*) at the level of the first pleckstrin homology domain, resulting in a premature protein termination and, possibly, in an mRNA nonsense-mediated decay. In general, a truncating mutation in a well-known causative gene is assumed to be pathogenic and predictive of phenotype. Additionally, in this case, it is noteworthy that the Pro610 residue has been previously reported as the target of a missense mutation (p.Arg610Gln) and found to segregate with the AAS phenotype in affected males and carrier females in a family.¹⁶ Due to the absence of description of hotspots or common mutations in the FGD1 gene, the report of a site suspected to be more preferentially involved in mutational events may be of interest.

Finally, the identification of 16p13.11 microduplications in the proband and in his mother adds an intriguing variable and raises questions about the coexistence of two genetic variants and their relative weight in the expression of the phenotype.

With regard to the 16p13.11 microduplication itself, the clinical relevance appears uncertain, as carriers can be totally normal or, on the contrary, may show a broad range of abnormalities, most commonly behavioural problems.⁷ Duplications and deletions at 16p13.11 (CNVs) are believed incompletely penetrant pathogenic variants with sex-limited effect on the penetrance and two-hit model have been proposed to possibly explain the underlying mechanism of clinical manifestations.^{6 17}

As it is increasingly recognised that pathogenic mutations can present with profound differences in the phenotypical expressivity, possibly depending on genetic modifiers, we speculate if the microduplication may have worked as a substantial modifier of the condition in our family, changing the AAS typical phenotype resulting from the FGD1 mutation, in agreement with the previously supposed mechanism for the coexistence with the SOX5 gene, or another gene involved in developmental processes.⁶

The FGD1 protein role in this Italian family is still uncertain; may be involved with inactivation of cell division control protein 42 homolog remodelling extracellular matrix/transcriptional activation/modulators of development. Other interactive genes such as epidermal growth factor receptor 1 signalling pathway may contribute to pathophysiology, moreover, further study needs to be made for resolving this issue.⁵

The comorbidities to a syndromic pathology can be manifold, such as cardiovascular, respiratory, neurobehavioral or even audiological possibly associated especially in critically ill patients.¹⁸

In the family we report, we can observe that all dysmorphic features and behavioural manifestations present in the present patient are consistent with those previously reported for FGD1 mutations and just coincidental and without clinical significance the detection of a 16p13.11 microduplication.

Patient’s perspective.

Maybe having another family case initially scared me and made it difficult to accept the disease. As a parent, I was afraid that the child had a serious illness such as heart or kidney problems. The doctors helped me step by step to follow the child’s growth and together we learnt to understand his needs.

Learning points.

• To avoid initial errors in the diagnostic assessment that would cause incorrect patient identification and possible disturbances and comorbidities associated with the principled pathology, it is necessary to fully understand the different mechanisms that involve such a variable phenotypic expression.

• To adequately monitor psycho-physical development and auditory maturation and language acquisition, serial checks must be performed each in a less restricted manner in the absence of significant evolutionary or debilitating organic or functional anomalies.

• To control the pathology in which it is concerned, the close multidisciplinary collaboration that involves different specialist figures such as the paediatrician, the neurologist, the otolaryngologist, the cardiologist as well as the endocrinologist for precision medicine is necessary. These assumptions are necessary to guarantee better patient outcomes.