Fetal Alcohol Spectrum Disorders and differential diagnosis

The term FASD encompasses a highly heterogeneous phenotypic spectrum of variable severity, which can range from asymptomaticity to spontaneous miscarriage and which can be divided on the basis of the clinical signs in: Fetal Alcohol Syndrome (FAS), which represents the most severe clinical manifestation linked to the harmful effects of alcohol; partial fetal alcohol syndrome (pFAS); alcohol-related neurodevelopmental disorder (ARND); alcohol-related birth defects (ARBD).

Fetal Alcohol Syndrome (FAS)

FAS is the most severe clinical manifestation due to prenatal exposure to alcohol. The diagnosis of FAS is predominantly clinical and is based on the presence of the 3 key signs:

1. growth retardation (pre or postnatal),
2. presence of characteristic facial dysmorphisms,
3. abnormalities in the central nervous system,

as well as the presence of suspected or confirmed intrauterine exposure to alcohol.

In children with FAS, peculiar facial features, discriminating in FAS diagnosis, have been identified. They include narrow palpebral fissures, long and flat philtrum and thin upper lip. Less frequently, epicanthus, long and narrow forehead, maxillary and mandibular hypoplasia, flat nose root and micrognathia may be present. However, it is important to remember that none of these alterations, taken individually, are pathognomonic of FAS and that the dysmorphic features become less and less evident with increasing age.

Children with FAS exhibit central nervous system dysfunction of varying degrees, which may include structural, neurological, or functional abnormalities or combinations thereof. Among the structural anomalies, microcephaly is one of the peculiar characteristics; among others, abnormalities of the corpus callosum and cerebral/cerebellar atrophy were found. Behavioral and cognitive deficits, developmental delay, memory and attention problems, hyperactivity and sleep disturbances are very common. Mental retardation, motor disability and speech disorders are also often present.

There is no treatment for FAS and the therapies implemented are only supportive. However, it has been shown that early diagnosis can reduce the occurrence of secondary disabilities such as isolation, lack of independent life and problems with work.

Other kinds of FASD

• Partial fetal alcohol syndrome (pFAS)

This category includes all those subjects who do not fully meet the FAS criteria, but have a history of exposure to alcohol, peculiar dysmorphisms and alterations of the central nervous system.

• Alcohol-related neurodevelopmental disorder (ARND)

This category includes all those individuals who have a history of prenatal alcohol exposure and problems with neurocognitive development, adaptive functioning and behavioral regulation, but who do not have facial dysmorphism and growth deficiency.

• Alcohol-related birth defects (ARBD)

These individuals have structural congenital malformations that can affect organs such as kidneys, heart, bones, brain, eyes and ears. These patients may also have other signs of FASD.

The incidence of FASD is very varied and may depend on economic, social and cultural factors, such as the predisposition to drink. Unfortunately, there are not many studies that investigate this aspect even though it is estimated that in Europe the incidence is 1-3: 10,000, while in the USA it is 2-7: 1000 for the FAS and 2-5% for the FASD. In Italy, the only available data is that of a Lazio study on six-year-old children which estimates the prevalence of FAS at 3.7-7.4: 1000 and of FASD at 2-4%.

Since none of the signs of FASD are pathognomonic, other possible causes for the patients’ phenotype need to be ruled out. Among the differential diagnoses of FASD there are some acquired pathologies such as toluene or anticonvulsant embryopathy, fetal syndromes due to drug intake, effects on the fetus of maternal phenylketonuria. However, it is also necessary to exclude the presence of congenital syndromes such as microdeletion/duplication syndromes or other syndromes of genetic origin.

In particular, among the genetic syndromes that have partially overlapping features to FAS we find:

Aarskog syndrome

Aarskog syndrome, also known as faciodigitogenital dysplasia, is a X-linked recessive disease caused by mutations in the FGD1 gene. It is characterized by short stature, characteristic facies including hypertelorism, anteverted nostrils, long philtrum, downslanting palpebral fissures, and midface hypoplasia, genital and digital anomalies. Most patients do not have mental retardation, although some may have neurobehavioral abnormalities. Heterozygous females may have some very subtle signs.

Noonan syndrome

Noonan syndrome is an autosomal dominant inherited disease characterized by congenital heart defects, short stature, varying degrees of developmental delay, and characteristic facies including broad forehead, hypertelorism, downslanted palpebral fissures, and posteriorly rotated ears. The phenotype is very variable and epicanthus and depressed nasal bridge may also be present among the dysmorphisms. Noonan syndrome is due in most cases to mutations in the PTPN11 gene, less commonly to mutations in SOS1, RAF1, RIT1 and KRAS, very rarely to mutations in genes such as BRAF, LZTR1, MAP2K1, NRAS, MRAS, RRAS and SOS2. Mutations in PPP1CB, RASA2, A2ML1, CBL and SHOC2 are associated with a Noonan-like phenotype.

Cornelia de Lange syndrome

Cornelia de Lange syndrome is a multisystem disorder encompassing mild to severe phenotypic spectrum characterized by poor growth, developmental delay, hypertrichosis, and characteristic facial dysmorphisms. These include the synophrys, short depressed nasal bridge with anteverted nostrils, microcephaly, micrognathia, long philtrum, and thin lips. Cornelia de Lange syndrome is due to heterozygous mutations in the NIPBL, RAD21, SMC3, and BRD4 genes, or to hemizygous mutations in the HDAC8 and SMC1A genes.

Dubowitz syndrome

Dubowitz syndrome is a systemic disease characterized by mental and growth retardation (including prenatal), multiple congenital anomalies and immunological defects, as well as peculiar facial features such as broad forehead, narrow palpebral fissures, ptosis, wide and flat nasal root, hypertelorism and epicanthus. Unfortunately, the etiology is not known, although it appears to be transmitted in a recessive manner.

Williams-Beuren syndrome

Williams-Beuren syndrome is a neurobehavioral disorder due to a 1.5-1.8 Mb microdeletion on chromosome 7q11.23, which includes approximately 28 genes. It is characterized by cardiovascular problems (especially supravalvular stenosis of the aorta), peculiar appearance of the face (small head, broad forehead, narrow palpebral fissures, long philtrum, epicanthus), developmental delay of varying degrees and growth retardation.

22q11.2 microdeletion syndrome

22q11.2 microdeletion syndrome, which includes velo-cardio-facial syndrome and DiGeorge syndrome, is a chromosomal disorder due to a 1.5-3 Mb microdeletion of the 22q11.2 region. It is a condition with high phenotypic variability characterized by congenital heart abnormalities, hypocalcemia, typical facies with small mouth, narrow palpebral fissures, small pinnae, prominent nose, hypertelorism and micrognathia, low birth weight, neurodevelopmental deficit and disorders of the immune system.

Blepharophimosis, Ptosis, and epichantus inversus (BPES)

BPES is a rare genetic syndrome characterized mainly by 4 eyelid abnormalities: narrow palpebral fissures (blepharophimosis), inverse epicanthus, drooping eyelids (ptosis) and increased distance between the inner corners of the eyes (telecanthus). There are two forms of BPES: type 1 is associated with female infertility, while type 2 is characterized only by the ocular phenotype. This syndrome is due to heterozygous mutations in the FOXL2 gene, although cases of homozygosity have rarely been reported.

 3-M syndrome

La sindrome 3M è una malattia genetica rara a trasmissione autosomica recessiva caratterizzata da un forte ritardo della crescita pre e post-natale, basso peso alla nascita, sviluppo psicomotorio normale e dismorfismi distintivi che comprendono viso triangolare, fronte prominente, l’ipoplasia mediofacciale, filtro lungo, radice del naso appiattita e labbra carnose. La maggior parte dei pazienti ha mutazioni nel gene CUL7, più rare sono le mutazioni nei geni OBSL1 e CCDC8.

3M syndrome is a rare, autosomal recessive genetic disorder characterized by severe pre- and postnatal growth retardation, low birth weight, normal psychomotor development and distinctive dysmorphisms including triangular face, prominent forehead, midfacial hypoplasia, long philtrum, depressed nasal bridge and full lips. Most patients have mutations in the CUL7 gene, rarely the mutations occur in the OBSL1 and CCDC8 genes.

Smith-Lemli-Optiz syndrome

Smith-Lemli-Optiz syndrome is a rare, autosomal recessive genetic disorder due to mutations in the DHCR7 gene. It is characterized by growth retardation, mental retardation and behavioral abnormalities such as hyperactivity and autistic traits, congenital malformations such as microcephaly, characteristic facies (with ptosis, long philtrum, wide nasal bridge with short root, micrognathia), syndactyly and genital anomalies.

Peters-plus syndrome

Peters plus syndrome is a rare, autosomal recessive genetic disorder due to mutations in the B3GLCT gene. It is characterized by ocular anomalies including Peters’ anomaly, peculiar facies with narrow palpebral fissures and cupid’s arch upper lip, ear anomalies, developmental delay and intellectual disability.

Other genetic syndromes that may have a phenotype partially overlapping  with FASD include Bloom syndrome (RECQL3 gene), campomelic dysplasia (SOX9 gene), 15q microduplication syndrome, Opitz-Kaveggia syndrome (MED12 gene), Floating-Harbor syndrome (SRCAP gene), geleophysical dysplasia 1 (ADAMTSL2 gene), Kabuki syndrome 1 (KMT2D), 17p13.3 microdeletion syndrome and Opitz GBBB syndrome (MID1 and SPECC1L genes).

The diagnosis of FAS must be “of exclusion”, that is, it must occur only after having discarded all the other possible causes of the patient’s phenotype, in the presence of a suspected or confirmed prenatal exposure to alcohol. For this reason it is important, after having performed the diagnostic tests for images, the audiometric and visual tests and having evaluated the case from a multi-specialized point of view (psychological, neurological and pediatric) to perform genetic tests such as the Array-CGH or the karyotype. These investigations are aimed at excluding any syndromes of genetic origin due to structural chromosomal alterations, but it would also be recommended to perform the whole exome sequencing (EXOME 60MB), to exclude other genetic pathologies due to point mutations.

Recommended panel testing at Breda Genetic:

Differential diagnosis for Fetal alcohol syndrome, extended (A2ML1, ADAMTSL2, B3GLCT, BRAF, BRD4, CBL, CCDC8, CUL7, DHCR7, FGD1, FOXL2, HDAC8, KMT2D, KRAS, LZTR1, MAP2K1, MED12, MID1, MRAS, NIPBL, NRAS, OBSL1, PPP1CB, PTPN11, RAD21, RAF1, RASA2, RECQL3, RIT1, RRAS, SHOC2, SMC1A, SMC3, SOS1, SOS2, SOX9, SPECC1L, SRCAP)