Table of Contents  

Hubaishi, Cherifi, Taka, Ashoor, and Paladini: Aarskog–Scott syndrome – prenatal ultrasound diagnosis in a case with positive family history

Established facts

Aarskog–Scott syndrome (AAS) is a rare developmental disorder inherited mainly as an X-linked recessive trait, with mutations of the FGD1 gene detected in a significant number of cases.

This condition is characterized by facial (hypertelorism, blepharoptosis, palpebral fissure, small nose, broad philtrum), limb (brachydactyly, clinodactyly, interdigital webbing, broad thumbs and big toes) and genital anomalies (shawl scrotum, undescended testis), and a disproportionate acromelic short stature. Mild to moderate mental retardation and attention deficit may be associated in a significant proportion of cases.

Novel insights

We demonstrate that, in families at risk, AAS may be suspected on ultrasonography in the first trimester of pregnancy: facial clefts, brachydactyly, short digits and an increased upper-to-lower-segment ratio can all be detected by transvaginal ultrasound. Hence, in the absence of evidence on first trimester transvaginal sonography, couples at risk may be reassured that the presence of AAS in the fetus is unlikely.

Case description

MA, aged 32 years, gravida 4, parity 3, who had previously had three caesarean sections, was referred to our fetal medicine unit for an initial assessment of her fourth pregnancy. Her husband and two male children were all diagnosed with AAS after the birth of the third child.

The patient’s first pregnancy resulted in an emergency caesarean section for failure to progress. A male infant weighing 2.2 kg was delivered and diagnosed after birth with cleft lip and palate. Examination revealed a dysmorphic face, hypertelorism, ptosis of the eyelids, low-set ears and disproportionate short stature with broad, short hands and feet (brachydactyly). A diagnosis could not be made at the time owing to the rarity of the genetic syndrome.

The patient’s second pregnancy terminated in emergency caesarean section for failure to progress, and resulted in delivery of a healthy female baby weighing 2.1 kg.

In her third pregnancy the patient had an elective caesarean section because of her previous two caesarean sections. The baby, another boy, had the same features as the first baby and also had undescended testes.

The patient did not report any major anomalies or signs of mental retardation in her husband or two male children. In view of the risk of recurrence, genetic testing (polymerase chain reaction and sequencing analysis) was performed and identified a familial mutation in the FGD1 gene (c.53del–p.Pro18Argfs*106), for which the mother was heterozygous and the two boys homozygous.

In view of her history, the patient was referred to the Fetal Medicine Unit in Dubai Hospital, at 13+4 gestational weeks. Transvaginal ultrasound was carried out at 13+4 gestational weeks and revealed a flat facial profile with a small nose and a slightly increased nuchal translucency (Figure 1a) on the mid-sagittal view of the fetal head and a unilateral cleft lip and palate on an axial view (Figure 1b). Evaluation of the skeleton showed short, broad hands with brachydactyly (Figure 1c) and an increased upper-to-lower-segment ratio (Figure 1d). All these features are consistent with AAS.

FIGURE 1

Transvaginal ultrasound at 13+4 gestational weeks. (a) Flat facial profile with small nose (arrow) and slightly increased nuchal translucency (3.0 mm; arrowhead). (b) Axial view of the face showing cleft lip and palate (arrowhead). (c) Broad hand with brachydactyly (arrows). (d) Subjective impression of reduced length of the lower limbs.

HMJ-678-fig1.jpg

The patient was counselled about the likely recurrence of the syndrome in her fourth pregnancy. Chorionic villus sampling was discussed but declined by the patient; monthly follow-up scans were then scheduled. Fetal growth remained within the range for gestational age, with long bones at the second to fifth centile throughout pregnancy. Male sex was sonographically confirmed at 16 weeks. A caesarean section was carried out at 39 weeks. The baby weighed 2800 g (no growth retardation). On initial physical examination, additional features consistent with AAS were noted, in particular hypertrichosis, widow’s peak, hypertelorism and clinodactyly (Figure 2).1 The presence of a unilateral cleft lip and palate (see Figure 2a) and brachydactyly (see Figure 2b) was also confirmed. Genetic testing (FGD1 gene sequencing) was carried out after birth and confirmed the presence of the familial mutation (c.53del–p.Pro18Argfs*106) in the neonate, genetically confirming that he has AAS.

FIGURE 2

The neonate on the first day of life. (a) Hypertrichosis, widow’s peak, hypertelorism and cleft lip and palate are evident. (b) Short, broad hand with brachydactyly. (c) Increased upper-to-lower-body ratio.

HMJ-678-fig2.jpg

Conclusion

Aarskog–Scott syndrome, which is also known as faciogenital dysplasia, is a rare developmental disorder, with fewer than 100 cases reported since its first description in 1970.1 The condition is characterized by facial, limb and genital features, and a disproportionate acromelic short stature. In most cases it is inherited as an X-linked recessive trait, which means that all male babies are affected and females are carriers, and may transmit the disease to their male offspring. Although mutations in the FGD1 gene (faciogenital dysplasia 1 gene; Xp11.21) have been found in a significant number of cases, AAS is a genetically heterogeneous condition24 and, therefore, the diagnosis is mainly clinical and based on physical examination. The mutation described here is a novel variant not previously described in the literature.4 However, because it is predicted to create a premature stop codon, and therefore produce a truncated FGD1 protein, it is pathogenic, as evident from the phenotype.

In the present case, we demonstrate that some of the typical features of the syndrome, such as a flat profile with a small nose or cleft, may be detected as early as the end of the first trimester of pregnancy. However, the key point is the positive family history. In fact, most of the findings described in this report are not specific for AAS, being present also in other syndromic conditions. A prospective diagnosis of AAS in the absence of a family history is therefore unlikely to be achieved in utero.

An important finding is that all the described features were already present as early as the 13th week of gestation. This piece of information can be used while counselling families with a history of AAS; in fact, in these cases, early transvaginal ultrasound carried out by an expert may also be employed to reassure the couple that, if none of the sonographically recognizable features of AAS is detected, it is highly likely that the fetus is not affected.

Genetic investigation is of limited value, partly because of the genetic heterogeneity and because the condition is known and generally accepted in the carrier families and, therefore, genetic testing, both pre- and postnatal, would make little difference in the management of the pregnancy or the affected individuals. This concept is reinforced by the fact that there is no way to predict the presence of neurodevelopmental delay or attention deficits after birth, considering also that mental retardation, when present, is never severe.

In conclusion, we have described the early prenatal ultrasound diagnosis of AAS at 13 weeks’ gestation in a family with a positive history, and confirmed it by finding the already-known familial pathogenetic variant of the FDG1 gene in the neonate, at birth. This leads to a proposal that in families with a positive history early scanning may be used to reassure the couple that the fetus is unlikely to be affected – provided that there are no suspicious findings.

References

1. 

Aarskog D. A familial syndrome of short stature associated with facial dysplasia and genital anomalies. J Pediatr 1970; 77:856–61.

2. 

Berman PA, Desjardins C, Fraser FC. Inheritance of the Aarskog syndrome. Birth Defects Orig Art Ser 1974; 10:151–9.

3. 

Orrico A, Galli L, Clayton-Smith J, Fryns JP. Clinical utility gene card for: Aarskog–Scott syndrome (faciogenital dysplasia) – update 2015. Eur J Hum Genet 2015; 23.

4. 

Völter C, Martínez R, Hagen R, Kress W. Aarskog–Scott syndrome: a novel mutation in the FGD1 gene associated with severe craniofacial dysplasia. Eur J Pediatr 2014; 173:1373–6.


Comments on this article



View all comments  |  Add comment 





Home  Editorial Board  Search  Current Issue  Archive Issues  Announcements  Aims & Scope  About the Journal  How to Submit  Contact Us
Find out how to become a part of the HMJ  |   CLICK HERE >>
© Copyright 2012 - 2013 HMJ - HAMDAN Medical Journal. All Rights Reserved         Website Developed By Cedar Solutions INDIA