a newborn with cleft palate associated to PTEN-Hamartoma-Tumor syndromeUlf Nestler1, Daniel Gräfe2, Vincent Strehlow3, Robin-Tobias Jauss3, Andreas Merkenschlager4, Annika Schönfeld5 and Florian Wilhelmy11Department of Neurosurgery, University Hospital, Leipzig, Germany2Institute for Pediatric Radiology, University Hospital, Leipzig, Germany3Institute for Medical Genetics, University Hospital, Leipzig, Germany4Division of Neuropediatrics, University Hospital, Leipzig, Germany5Department of Oral and Maxillofacial Surgery, University Hospital, Leipzig, Germanyulf.nestler@medizin.uni-leipzig.de daniel.graefe@medizin.uni-leipzig.de vincent.strehlow@medizin.uni-leipzig.de robin-tobias.jauss@medizin.uni-leipzig.de andreas.merkenschlager@medizin.uni-leipzig.de annika.schoenfeld@medizin.uni-leipzig.de florian.wilhelmy@medizin.uni-leipzig.dePTEN Hamartoma Tumor Syndrome (PHTS) encompasses a range of syndromes, including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and Lhermitte-Duclos disease. These syndromes are caused by loss-of-function and null variants in the phosphatase and tensin homolog (PTEN) tumor suppressor gene on chromosome 10q23.31, leading to a lifelong predisposition for tumor development.1 The genotype-phenotype correlation is weak, the penetrance is age-dependent and the description of phenotype expression is still evolving.2,3Initial description of Cowden syndrome included orofacial dysmorphism, and facial and oral examinations can reveal aberrations in about one third of cases.4,5 Recent pediatric publications have primarily focused on skin stigmata, macrocephaly and developmental delay, partly influenced by the subspecialty of the initially examining physician (Tab. 1). Here we report on the phenotypic spectrum with a case of cleft palate associated to PHTS in a newborn.The male infant was born by planned cesarean section at 38 weeks of gestation due to polyhydramnios and macrocephaly. Birth weight was 3972 g (1.5 z), length 52 cm (0.4 z) and head circumference 40 cm (3.6 z).The patient is the third child of non-consanguineous parents. His 6-year-old brother had suffered from a single epileptic seizure with suspected self-limited focal epilepsy of childhood (“Rolandic”). The 4-year-old sister and the father are healthy, while the mother has ulcerative colitis and a cousin of the maternal grandmother had a cleft palate and lip.Postnatal respiratory adaptation was prolonged and complicated by hypoglycemic episodes. A cleft soft palate was detected shortly after birth, and together with macrocephaly prompted genetic counseling. Whole exome sequencing (WES) with subsequent segregation analysis of the parents revealed a heterozygous, de novo , null variant c.184A>T, p.(Lys62*) in the PTEN gene. The variant has previously been reported as pathogenic (ClinVar-ID: 1069915).The child was referred to an oromaxillofacial surgeon who scheduled surgical closure at 10 months and initiated MR-Imaging to rule out hydrocephalus before surgery (Fig. 1). Examination at 10 months revealed brown skin patches on both knees and soles, without penile freckling. Head circumference was 50 cm (2.8 z), and no partial overgrowth was observed. A persistent foramen ovale and ductus arteriosus, and mild mitral insufficiency were noted. Despite starting to roll over since 6 months of age, the boy was showing mild motor development delay, not yet being able to sit. A detailed diagnostic work-up for PHTS-related symptoms, including thyroid abnormalities, gastrointestinal polyposis and autism spectrum disorder was planned according to German guidelines.6PTEN Hamartoma Tumor Syndrome presents a diagnostic challenge. On one hand, patients have tumor predisposition with a 6% risk of developing a malignant tumor in childhood. On the other hand, screening for cancer or benign neoplasms in young children poses additional risks by repeated anesthesia or invasive procedures. Thus the appropriate timing of routine, guideline-driven diagnostic evaluations remains a matter of debate.7Macrocephaly is often an obvious symptom and can be observed prenatally. Transfontanellar ultrasonography, and cerebral MRI in older children are indicated to rule out hemorrhage, hydrocephalus or tumors. Although MRI findings are characteristic and present in up to 40 % of patients, they are not specific for PHTS (Fig. 1).7 Hydrocephalus in the setting of cranial dysmorphism in pediatric PHTS can result from Chiari malformation or arise secondary from dysplastic cerebellar gangliocytoma in Lhermitte-Duclos disease. However, in review of the 159 patients in table 1, only one ventriculo-peritoneal shunt procedure for pseudotumor cerebri was reported (0.6%).8Skin stigmata, such as lipoma, hemangioma or hamartoma, trichilemmoma and café-au-lait spots are detectable by inspection. These signs are generally well-documented, examination results appear in 155 from 159 patients. The occurrence of subcutaneous lipoma, which is a rare finding in children, particularly when combined with macrocephaly, should raise suspicion of PHTS and prompt genetic testing.5Reports of PTEN-associated cleft palate are scarce, although orofacial dysmorphism and a high-arched palate are present in 27% to 34% of cases. A single case of bifid uvula was described in 2007.9 Considering that up to 31% of cases present with oral mucosal papillomatosis, and that oral hyperkeratosis was described as part of Cowden syndrome, oral examination is an important adjunct in diagnosing PHTS.10 However, our overview suggests that oral signs are less frequently emphasized in the diagnostic process compared to the more prominent symptoms, with oral findings reported in only 24 cases from 159.Data collection and analysis in PHTS are limited by the retrospective nature of most case reports and reviews. It remains difficult to predict tumor risk during infancy or to estimate, how many patients live with a pathogenic variant in PTEN , without ever requiring medical attention. We advocate for broad genetic testing like WES with a low threshold of suspicion, to anticipate developmental delays, to potentially detect tumor growth at an early stage and to support patients and families in managing this rare, burdensome disease.CONFLICT OF INTERESTThe authors declare that there is no conflict of interest.ETHICAL STATEMENTThe mother of the patient has given written consent to the scientific publication of the case.REFERENCES1. Leibowitz MS, Zelley K, Adams D, et al. Neuroblastoma and cutaneous angiosarcoma in a child with PTEN hamartoma tumor syndrome.Pediatr Blood Cancer. 2022;69(10):e29656. doi:10.1002/pbc.296562. Macken WL, Tischkowitz M, Lachlan KL. PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature. Am J Med Genet C Semin Med Genet. 2019;181(4):591-610. doi:10.1002/ajmg.c.317433. Martinez-Rios C, De Leon Benedetti LS, Tierradentro-Garcia LO, Kilicarslan OA, Caro-Dominguez P, Otero HJ. Imaging findings of children with PTEN-related hamartoma tumor syndrome: a 20-year multicentric pediatric cohort. Pediatr Radiol. 2024;54(7):1116-1127. doi:10.1007/s00247-024-05922-84. LLOYD KM 2nd, DENNIS M. Cowden’s disease. A possible new symptom complex with multiple system involvement. Ann Intern Med. 1963;58:136-142. doi:10.7326/0003-4819-58-1-1365. Martin H, Bessis D, Bourrat E, et al. Cutaneous lipomas and macrocephaly as early signs of PTEN hamartoma tumor syndrome.Pediatr Dermatol. 2020;37(5):839-843. doi:10.1111/pde.142656. Plamper M, Gohlke B, Woelfle J. PTEN hamartoma tumor syndrome in childhood and adolescence-a comprehensive review and presentation of the German pediatric guideline. Mol Cell Pediatr. 2022;9(1):3. Published 2022 Feb 21. doi:10.1186/s40348-022-00135-17. Smpokou P, Fox VL, Tan WH. PTEN hamartoma tumour syndrome: early tumour development in children. Arch Dis Child. 2015;100(1):34-37. doi:10.1136/archdischild-2014-3059978. Plamper M, Born M, Gohlke B, et al. Cerebral MRI and Clinical Findings in Children with PTEN Hamartoma Tumor Syndrome: Can Cerebral MRI Scan Help to Establish an Earlier Diagnosis of PHTS in Children?.Cells. 2020;9(7):1668. Published 2020 Jul 10. doi:10.3390/cells90716689. Yotsumoto Y, Harada A, Tsugawa J, et al. Infantile macrocephaly and multiple subcutaneous lipomas diagnosed with PTEN hamartoma tumor syndrome: A case report. Mol Clin Oncol. 2020;12(4):329-335. doi:10.3892/mco.2020.198810. Fardal Ø, Nevland K, Johannessen AC, Vetti HH. The PTEN hamartoma tumor syndrome: how oral clinicians may save lives. Clin Adv Periodontics. 2023;13(1):21-26. doi:10.1002/cap.1019611. Bregvadze K, Jabeen S, Rafi SM, Tkemaladze T. The complexity of phosphatase and tensin homolog hamartoma tumor syndrome: A case report.SAGE Open Med Case Rep. 2024;12:2050313X241245317. Published 2024 Apr 6. doi:10.1177/2050313X24124531712. Martín-Valbuena J, Gestoso-Uzal N, Justel-Rodríguez M, et al. PTEN hamartoma tumor syndrome: Clinical and genetic characterization in pediatric patients. Childs Nerv Syst. 2024;40(6):1689-1697. doi:10.1007/s00381-024-06301-213. Ciaccio C, Saletti V, D’Arrigo S, et al. Clinical spectrum of PTEN mutation in pediatric patients. A bicenter experience. Eur J Med Genet. 2019;62(12):103596. doi:10.1016/j.ejmg.2018.12.00114. Plamper M, Gohlke B, Schreiner F, Woelfle J. Phenotype-Driven Diagnostic of PTEN Hamartoma Tumor Syndrome: Macrocephaly, But Neither Height nor Weight Development, Is the Important Trait in Children.Cancers (Basel). 2019;11(7):975. Published 2019 Jul 11. doi:10.3390/cancers1107097515. Kato K, Mizuno S, Inaba M, et al. Distinctive facies, macrocephaly, and developmental delay are signs of a PTEN mutation in childhood.Brain Dev. 2018;40(8):678-684. doi:10.1016/j.braindev.2018.04.00816. Hansen-Kiss E, Beinkampen S, Adler B, et al. A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children.J Med Genet. 2017;54(7):471-478. doi:10.1136/jmedgenet-2016-10448417. Busa T, Milh M, Degardin N, et al. Clinical presentation of PTEN mutations in childhood in the absence of family history of Cowden syndrome. Eur J Paediatr Neurol. 2015;19(2):188-192. doi:10.1016/j.ejpn.2014.11.012LEGENDSTABLE 1: Childhood PTHS symptoms reported over the last ten years, listed according to the number of patients examined for each specific symptom