Clinical Guidance

Although the number of affected individuals in whom pathogenic variants in HOXA13 have been identified is small, some genotype-phenotype correlations are emerging. The limb malformations in individuals with the heterozygous pathogenic nonsense variants in either exon 1 or 2 or a polyalanine expansion in exon 1 are similar to those described in individuals with a cytogenetic deletion of the HOXA cluster and adjacent genomic DNA , suggesting that these typical features result from HOXA13 haploinsufficiency. Minor differences may be attributable to effects of other genetic loci or stochastic variables. Generally speaking, HOXA13 homeodomain pathogenic missense variants appear to produce more severe features or unusual digital malformations; the variant p.

Source: GeneReviews — "Hand-Foot-Genital Syndrome"

Penetrance

Skeletal defects are 100% penetrant. Penetrance for urogenital malformations is greater than 50% overall and may be greater for affected females.

Source: GeneReviews — "Hand-Foot-Genital Syndrome"

Diagnostic Criteria

Suggestive Findings

Hand-foot-genital syndrome should be suspected in individuals with the following clinical and radiographic features.

Limb Malformations

Bilateral thumb and great-toe hypoplasia are the hallmark malformations, caused primarily by shortening of the distal phalanx and/or the first metacarpal or metatarsal. Shortening is often mild to moderate but on occasion may be more severe and may cause shortening of the distal phalanx of other digits (see , (family 5), and ). Additional findings that may be present:

Source: GeneReviews — "Hand-Foot-Genital Syndrome"

Differential Diagnosis

Table 2.

Disorders to Consider in the Differential Diagnosis of Hand-Foot-Genital Syndrome (HFGS)

Clinical Features Overlapping w/HFGS | Differential DiagnosisDisorder | Gene(s) /Genetic Mechanism | MOI | Clinical Features of Differential Diagnosis Disorder Distinguishing It from HFGS

Thumb hypoplasia, often in addition to other anomalies | Fanconi anemia | 21 genes | ARADXL | • Bone marrow failure

• risk of malignancy

Rothmund-Thomson syndrome

| RECQL4 | AR | • Rash, poikiloderma

• Cataracts

• risk of malignancy

Holt-Oram syndrome

| TBX5 | AD | Cardiac malformation

Lacrimo-auriculo-dento-digital syndrome (OMIM 149730) | FGFR3

FGF10

FGFR2

| AD | • Characteristic facial features

• Dental anomalies

Nager syndrome (OMIM 154400) | SF3B4 | AD | Characteristic facial features w/ear anomalies

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hand-foot-genital syndrome (HFGS), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Hand-Foot-Genital Syndrome

System/Concern | Evaluation | Comment

Musculoskeletal

| Physical exam radiographs of hands feet | To evaluate for abnormalities that may affect function

Renal

| Urologic assessment of bladder, ureter function, urethral competence position | Incl renal ultrasound VCUG for UPJ obstruction

Gynecologic

| • Gynecologic exam prior to menstruation or pregnancy.

• Eval may incl ultrasound, hysterosalpingogram, hysteroscopy, sonohysterogram, MRI, or other imaging studies.

| • For evidence of incomplete mllerian fusion, longitudinal vaginal septum, or extremely small hymenal opening

• Such studies could be accomplished at the same time as urologic imaging.

Other

| Consultation w/clinical geneticist /or genetic counselor |

UPJ = ureteropelvic junction; VCUG = voiding cystourethrogram

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with Hand-Foot-Genital Syndrome

Manifestation/Concern | Treatment | Considerations/Other

Bladder outlet abnormalities

| Urologic referral | For surgical correction ureteric implantation

Gynecologic anomalies

| Gynecologic referral | • Surgical removal of longitudinal vaginal septum is rar...

Source: GeneReviews — "Hand-Foot-Genital Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Hand-Foot-Genital Syndrome"

Surveillance Guidelines

Follow up with a urologist in the presence of vesicoureteral reflux and/or documented urinary tract infection is warranted.

Source: GeneReviews — "Hand-Foot-Genital Syndrome"