Frank-Ter Haar Syndrome

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Anshika Kondala, Safa Ibrahim, MD

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Safa Ibrahim, MD

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Disease Entity

Disease

Frank-Ter Haar syndrome (FTHS), also known as Ter Haar syndrome, is a rare autosomal recessive disorder caused by biallelic variants in SH3PXD2B, with craniofacial, skeletal, cardiac, and ocular abnormalities.[1,2] The literature spells the name inconsistently (Frank-ter Haar, Frank-Ter Haar, Frank ter Haar). This article uses Frank-Ter Haar throughout. The ocular hallmarks are megalocornea and congenital glaucoma.[2,3,4] Frank et al. described the first patient in 1973, and ter Haar et al. reported an affected family in 1982. The two phenotypes were later recognized as one entity.[5,6,7]

Etiology

By 2020, 40 patients with a clinical diagnosis had been reported, only 20 of whom had an identified SH3PXD2B variant.[8] In the gene-discovery study, homozygosity mapping across 12 families found SH3PXD2B mutations in seven.[1] Homozygous and compound heterozygous variants have since been reported, many found by exome sequencing.[9,10,11] Most affected children are born to consanguineous parents, and each sibling of an affected child has a 25% chance of being affected.[7,12] When the familial variants are known, testing at-risk siblings soon after birth can identify affected infants early and spare unaffected ones repeated examinations under anesthesia (EUA).[12]

SH3PXD2B encodes TKS4, a podosome adaptor protein needed for extracellular matrix remodeling and cell migration.[1,13] In the nee mouse, an Sh3pxd2b mutant, anterior segment dysgenesis with iridocorneal adhesions is followed by raised IOP and early-onset glaucoma, implicating podosomes in development of the iridocorneal angle.[14]

Diagnosis

History

A full history and physical should be performed. Patients must be asked about consanguinity, affected siblings, and known familial variants.[7,12] It is also important to ask about congenital heart disease and any previous anesthetic or airway problems.[7,15,16] Additionally, headaches may signal raised intracranial pressure.[7]

Clinical Manifestations/Physical Examination

The syndrome can be recognized in the newborn period.[3,11,17] An ophthalmologist who finds megalocornea with hypertelorism should look for the features below and refer to genetics.

System	Features to look for	Relevance to the ophthalmologist
Craniofacial	Brachycephaly, wide fontanelles, prominent forehead, hypertelorism, prominent eyes, full cheeks, small chin, protruding ears[2]	Craniosynostosis with raised intracranial pressure has been reported. Check the discs for papilledema[7,18]
Skeletal	Bowing of long bones, finger flexion deformities, prominent coccyx[2]	Supports the diagnosis
Cardiac	Mitral and aortic valve disease, ventricular septal defect, double-outlet right ventricle[7]	Relevant to anesthesia planning for EUA and surgery
Airway	Difficult tracheal intubation[15,16]	Anesthesia team should prepare for a difficult airway
Development	Developmental delay[2]	Choose visual assessment methods suited to developmental age

Ocular Findings

• Megalocornea, with or without glaucoma, is the most consistent ocular sign. It was present in all 9 molecularly confirmed patients assessed in the gene-discovery cohort.[1,2,7]
• Congenital glaucoma and ocular hypertension range from neonatal buphthalmos with corneal edema to ocular hypertension found on examination.[1,3,18]
• Buphthalmos with Haab striae, with corneal diameters of 13 and 15 mm asymmetric between the eyes, has been documented.[4]
• Angle anomaly: marked anterior iris insertion was seen at trabeculotomy,[3] consistent with the angle dysgenesis of the mouse model.[14]
• Hypertelorism and prominent eyes are part of the facial pattern.[1,2]
• Individually reported: colobomas of the iris, choroid, and retina, a myelinated retinal nerve fiber layer, papilledema from idiopathic intracranial hypertension, and refractive amblyopia.[18] High against-the-rule astigmatism, sensory exotropia, and retinal detachment have also been described.[4,19]
• Variable expression: three siblings with a confirmed SH3PXD2B deletion had neither megalocornea nor glaucoma.[7]

Diagnostic Procedures

Most young children need an EUA. The standard measurements are described in Primary Congenital Glaucoma.[12] Points specific to FTHS:

• Gonioscopy for anterior iris insertion and other angle anomalies.[3]
• Peripheral retina for coloboma and detachment, with B-scan ultrasonography when the fundus cannot be seen.[4,18,19]
• Optic disc margins for papilledema.[7,18]
• Anesthesia planning for cardiac disease and a possible difficult airway.[7,15,16]
• Molecular testing: SH3PXD2B or exome sequencing confirms the diagnosis.[9,11] A negative result does not exclude FTHS.[8]

Differential Diagnosis

The discriminating features of megalocornea and buphthalmos are covered in Megalocornea, Neuhauser Syndrome, and Primary Congenital Glaucoma.

The FTHS-specific point is that glaucoma is genuinely part of the phenotype. Isolated megalocornea is by definition non-glaucomatous, and Neuhauser syndrome is defined by megalocornea with intellectual disability rather than glaucoma. In FTHS, congenital glaucoma and ocular hypertension occur in a substantial subset of reported patients.[1,3,4,18] There are two important things to keep in mind:

• A normal IOP does not exclude the diagnosis or glaucoma. One reported child had an IOP of 18 mmHg in both eyes but advanced glaucomatous disc damage.[4] In infants, ocular enlargement, Haab striae, and cupping may matter more than the IOP value.[20]
• A normal IOP does not end surveillance. Ocular hypertension has been found on routine examination, and the mouse model develops glaucoma after birth.[14,18] The World Glaucoma Association (WGA) recommends regular lifelong monitoring in syndromes associated with childhood glaucoma.[20]

Management

General Treatment

No treatment trials or guidelines exist for FTHS, and the evidence consists of case reports.[3,4,8,18,19] Management follows childhood glaucoma guidance (see Primary Congenital Glaucoma), with regular lifelong monitoring and treatment of elevated IOP if it occurs.[20] Refractive correction and amblyopia therapy proceed alongside glaucoma care.[20]

Surveillance

No surveillance schedule has been published for FTHS. The intervals below come from guidance for primary congenital glaucoma and childhood glaucoma, applied to FTHS by extension.

Clinical situation	Interval in published guidance	Source	Application to FTHS
No glaucoma	Regular lifelong monitoring, with timed follow-up or EUA when the diagnosis or progression is uncertain	WGA consensus[20]	A child with FTHS and megalocornea meets CGRN glaucoma-suspect criteria[21]
No glaucoma, genetically at-risk child	Yearly glaucoma screening into young adulthood may be appropriate	GeneReviews[12]	This is a reasonable minimum, with more frequent examination when findings are borderline or changing
Infant or young child	Axial length at baseline, then about every 3–4 months. Measuring it is not by itself an indication for EUA	Primary Congenital Glaucoma	Most informative while the eye is still enlarging. Axial growth plateaus around age 3[22]
Glaucoma with IOP controlled	Typically every 3 months	GeneReviews[12]	Applies directly
After glaucoma surgery	At least every 3–4 months in young children or with less than 2 years of IOP control, then at least every 6 months, lifelong	Primary Congenital Glaucoma	Applies directly

What counts as change. The Childhood Glaucoma Research Network (CGRN) defines childhood glaucoma by two or more of the criteria below. A glaucoma suspect has one, including increased corneal diameter or axial length with normal IOP.[21] The full classification is in Childhood Glaucoma Research Network Classification and Epidemiology of Childhood Glaucoma. Because megalocornea is a baseline feature of FTHS, a single large corneal diameter is not evidence of glaucoma. Change over time is what matters.

Parameter	CGRN glaucoma criterion[21]	Interpretation in FTHS
IOP	Above 21 mmHg	Often unreliable in infancy,[20] and a normal value does not exclude glaucoma[4]
Optic disc	Progressive increase in cup-to-disc ratio, asymmetry of 0.2 or more with discs of similar size, or focal rim thinning	Important and sensitive for diagnosis and progression. Cupping often reverses after successful treatment[20]
Cornea	Haab striae, or diameter 11 mm or more in a newborn, over 12 mm under 1 year, or over 13 mm at any age	Megalocornea alone may exceed these values. Increasing diameter is the hallmark of glaucoma in early childhood, and serial measurement is most useful up to about age 3[20]
Refraction and axial length	Progressive myopia or myopic shift with an increase in ocular dimensions beyond normal growth	Axial length outside normal limits strongly suggests glaucoma, and continued elongation suggests inadequate control[20,22]
Visual field	Reproducible glaucomatous defect	Useful but challenging in children. Repeat testing to confirm defects[20]

It is beneficial to use the same anesthetic at each EUA so IOP readings are comparable.[20] After surgery, axial length is the most reliable objective index of progression, because corneal diameter stabilizes and cupping can be obscured by media opacity or reverse after IOP lowering.[22]

Medical Therapy

Medication is mainly a bridge to surgery. Drug choice and pediatric cautions are covered in Primary Congenital Glaucoma.[20] Given the cardiac disease reported in FTHS,[2,7] it is reasonable to discuss topical beta-blockers with the child's cardiologist.

Surgery

Procedure choice and technique follow Primary Congenital Glaucoma. Angle surgery is the procedure of choice in primary congenital glaucoma but generally succeeds less often in secondary childhood glaucomas. Trabeculectomy or a glaucoma drainage device is the next step after failed angle surgery.[20] 360-degree circumferential trabeculotomy may achieve greater success than conventional trabeculotomy.[23] Points specific to FTHS:

• Abnormal angle. Marked anterior iris insertion was found at trabeculotomy, and the mouse model shows iridocorneal adhesions.[3,14] Gonioscopy before surgery helps with planning.[20]
• Reported procedures. Bilateral trabeculotomy was performed uneventfully in a 21-day-old infant.[3] Trabeculotomy combined with trabeculectomy controlled IOP in a sibling pair.[4] One infant had refractory glaucoma.[8]
• Anesthesia. Difficult intubation has been reported,[15,16] and each surgery is an opportunity to record the full set of EUA measurements.

Refractive Error and Ambylopia

• Refractive amblyopia was reported in both siblings of one FTHS pair.[18] High against-the-rule astigmatism and asymmetric corneal enlargement have also been documented.[4,19]
• Need to perform cycloplegic refraction at each EUA or clinic visit.[20]
• Refractive correction alone can improve acuity in anisometropic and bilateral refractive amblyopia, and patching and atropine are standard next steps.[24]
• In the CLEVR-PCG randomized trial of 56 children aged 4–15 years after surgery for primary congenital glaucoma, rigid gas-permeable contact lenses gave greater improvement in acuity and contrast sensitivity than spectacles.[25] However, the trial did not include children with FTHS.
• Sensory exotropia has been reported.[19]

Prognosis

Visual outcome in congenital glaucoma depends on severity at diagnosis, response to surgery, and IOP control,[12] and IOP control and optic disc configuration over time are associated with final acuity.[26] In FTHS, surgery controlled IOP in one sibling pair, although one child already had advanced disc damage.[4] Glaucoma can also be severe and refractory.[8] Retinal detachment and amblyopia are other reported threats to vision.[4,18,19] Systemic prognosis varies: severe cardiovascular complications occurred in the original ter Haar family,[6] survival into adolescence with progressive valve disease has been reported,[7] and one infant died of respiratory failure at 4.5 months.[8]

Additional Resources

• EyeWiki: Primary Congenital Glaucoma, Megalocornea, Neuhauser Syndrome, Childhood Glaucoma Research Network Classification and Epidemiology of Childhood Glaucoma
• World Glaucoma Association, 9th Consensus: Childhood Glaucoma (summary consensus points)
• GeneReviews: Primary Congenital Glaucoma
• OMIM 249420: Frank-Ter Haar syndrome

References

1. Iqbal Z, Cejudo-Martin P, de Brouwer A, et al. Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar syndrome. Am J Hum Genet. 2010;86(2):254-261.
2. Maas SM, Kayserili H, Lam J, Apak MY, Hennekam RC. Further delineation of Frank-ter Haar syndrome. Am J Med Genet A. 2004;131(2):127-133.
3. Aktas Z, Karaca EE, Dogan N, Çakmak T, Unlu M, Tok L, Hasanreisoglu M. Congenital glaucoma as an ophthalmic manifestation of Frank-Ter Haar syndrome. Int Ophthalmol. 2014;34(2):351-354.
4. Ratukondla B, Prakash S, Reddy S, et al. A rare case report of Frank Ter Haar syndrome in a sibling pair presenting with congenital glaucoma. J Glaucoma. 2020;29(3):236-238.
5. Frank Y, Ziprkowski M, Romano A, et al. Megalocornea associated with multiple skeletal anomalies: a new genetic syndrome? J Genet Hum. 1973;21(2):67-72.
6. ter Haar B, Hamel B, Hendriks J, de Jager J. Melnick-Needles syndrome: indication for an autosomal recessive form. Am J Med Genet. 1982;13(4):469-477.
7. Bendon CL, Fenwick AL, Hurst JA, et al. Frank-ter Haar syndrome associated with sagittal craniosynostosis and raised intracranial pressure. BMC Med Genet. 2012;13:104.
8. Durand B, et al. A severe case of Frank-ter Haar syndrome and literature review: further delineation of the phenotypical spectrum. Eur J Med Genet. 2020;63(4):103857.
9. Zrhidri A, et al. Identification of two novel SH3PXD2B gene mutations in Frank-Ter Haar syndrome by exome sequencing: case report and review of the literature. Gene. 2017;628. PMID 28694206.
10. Massadeh S, Alhabshan F, AlSudairi HN, et al. The role of the disrupted podosome adaptor protein (SH3PXD2B) in Frank-Ter Haar syndrome. Genes (Basel). 2022;13(2):236.
11. Türkyilmaz A, Sager SG, Topcu B, Kaplan AT, Günbey HP, Akin Y. Novel SH3PXD2B variant identified by whole-exome sequencing in a Turkish newborn with Frank-Ter Haar syndrome. Clin Dysmorphol. 2022;31(1):45-49.
12. Abu-Amero KK, Edward DP. Primary congenital glaucoma. In: Adam MP, et al., eds. GeneReviews. Seattle: University of Washington; updated August 17, 2017.
13. Cejudo-Martin P, Courtneidge SA. Podosomal proteins as causes of human syndromes: a role in craniofacial development? Genesis. 2011;49(4):209-221.
14. Mao M, Hedberg-Buenz A, Koehn D, John SW, Anderson MG. Anterior segment dysgenesis and early-onset glaucoma in nee mice with mutation of Sh3pxd2b. Invest Ophthalmol Vis Sci. 2011;52(5):2679-2688.
15. Tommasino C, Albicini M. Anaesthesia and orphan diseases: difficult tracheal intubation in a child with Frank-ter Haar syndrome. Eur J Anaesthesiol. 2018;35(7):542-544.
16. Basaran I, Gozubuyuk E, Canbolat N, et al. Anesthetic management of scoliosis operation in a pediatric patient with Frank-ter Haar syndrome: a case report. Braz J Anesthesiol. 2021;71(2):181-183.
17. Femitha P, Joy R, Gane BD, Adhisivam B, Bhat BV. Frank-Ter Haar syndrome in a newborn. Indian J Pediatr. 2012;79(8):1091-1093.
18. Chang TC, Bauer M, Puerta HS, Greenberg MB, Cavuoto KM. Ophthalmic findings in Frank-ter Haar syndrome: report of a sibling pair. J AAPOS. 2017;21(6):514-516.
19. Furundaoturan O, Baris ME, Ayyıldız Emecen D, Demirkilinc Biler E. Retinal detachment in a child with Frank-ter Haar syndrome. Ophthalmic Genet. 2023;44(3).
20. Weinreb RN, Grajewski A, Papadopoulos M, Grigg J, Freedman S, eds. Childhood Glaucoma: The 9th Consensus Report of the World Glaucoma Association. Amsterdam: Kugler Publications; 2013. Summary consensus points.
21. American Academy of Ophthalmology, Pediatric Ophthalmology Education Center. Glaucoma: definitions and classification.
22. Longo R, Franzolin E, Gusson E, Chemello F, Panunzi S, Marchini G. The role of axial length and intraocular pressure in the follow-up of growing children with primary congenital glaucoma. J Clin Med. 2025;14(7):2152.
23. Gagrani M, Garg I, Ghate D. Surgical interventions for primary congenital glaucoma. Cochrane Database Syst Rev. 2020;8:CD008213.
24. Cruz OA, Repka MX, Hercinovic A, et al. Amblyopia Preferred Practice Pattern. Ophthalmology. 2023;130(3):P136-P178.
25. Jiang J, Hu Y, Zhu Y, et al. Visual outcomes of children with primary congenital glaucoma receiving different refractive corrections: the CLEVR-PCG randomized clinical trial. JAMA Ophthalmol. 2025;143(12):1006-1013.
26. Lee HJ, Kim YK, Jeoung JW, et al. Visual outcomes and associated factors of primary congenital glaucoma in children. Graefes Arch Clin Exp Ophthalmol. 2021;259:3445-3451.