Table of Contents

HK J Paediatr (New Series)
Vol 27. No. 2, 2022

HK J Paediatr (New Series) 2022;27:141-144

Case Report

The First Case of SUFU Related Gorlin Syndrome Presenting with Infantile Medulloblastoma in Hong Kong

VHT Yick, HM Luk


Gorlin syndrome (GS) is a rare, clinically and genetically heterogeneous autosomal dominant disorder primarily characterised by early onset of odontogenic keratocysts, multiple basal cell carcinomas and palmar or plantar pits. Two genetic mutations, namely PTCH1 and SUFU, have been described to be the culprit of such syndrome. PTCH1 and SUFU, as the two groups of GS, have different underlying mechanism and clinical presentation. In particular, the SUFU gene mutation is associated with higher risk of developing infantile medulloblastoma and jaw cysts. However, individuals presenting with an infantile medulloblastoma are mostly presumed to be sporadic. Here we have reported the first case of SUFU related Gorlin syndrome presenting with infantile medulloblastoma in Hong Kong. The clinical phenotype and underlying mechanism have also been discussed.

Keyword : Gorlin syndrome; Infantile medulloblastoma; SUFU


Medulloblastoma is one of the major causes of morbidity and mortality in paediatric oncology. Historically, classification of medulloblastoma is based on immunohistochemistry. Recent technological advancement in molecular testing redefined the classification into four groups, namely wingless (Wnt), sonic hedgehog (Shh), Group 3 and Group 4.1 Different subgroups of medulloblastoma have difference in clinical presentation, age of onset and recurrence pattern. In particular, recent testing revealed the SUFU gene, together with the PTCH1 gene, are strongly associated with the sonic hedgehog pathway, and subsequently Gorlin syndrome (GS)

with the presentation of early onset of medulloblastoma. This article reports a case of Gorlin syndrome first presenting with infantile medulloblastoma. Diagnosing Gorlin syndrome is important as the patient are highly susceptible to basal cell carcinoma, congenital skeletal abnormalities and other tumourigeneses.

Case Report

The proband is now a 20-year-old gentleman. He was the first child of the family born at full term with birth weight of 3.52 kg. His perinatal history was unremarkable, except he experienced frequent repeated vomiting from 1 month of age. His head circumference was increased from 50th to 90th percentile at 5 months of age. Imaging at the same age showed tumour at the posterior cranial fossa. He had underwent subtotal excision at 1 year old with histology confirmed to be medulloblastoma in year 2000. However, no histological subclassification was performed at that time. He was put on postoperative standard risk medulloblastoma Baby POG Chemotherapy protocol. The chemotherapy regime included Vincristine, Cisplatin and Cyclophosphamide. But parents refused postoperative radiotherapy. He was in complete remission afterwards. On subsequent follow up, he was noted to have features of Gorlin syndrome such as macrocephaly and dermal pits on palmar and plantar region (Figure 1). He was then referred to the Clinical Genetic Service for assessment.

Genetic Testing shows that he has maternal inherited heterozygous pathogenic splice site variant c.684-1G>A in SUFU gene (NM_016169.3), therefore substantiated the molecular diagnosis of SUFU related Gorlin syndrome. After surgical intervention, he has mild residual cerebellar deficit with no intellectual disability. There was no dental, skeletal and skin cancer on follow up. And there is no family history of cancer.



Recently, an international consensus was reached for the molecular subgrouping of paediatric medulloblastomas, which has different genetic causes and therefore different recurrence and metastasis.2 The four groups include wingless (Wnt), sonic hedgehog (Shh), Group 3 and Group 4. It was found that Wnt tumours are very likely to have an onset between 6-12 years old, while Shh tumours age of onset ranges from infant to adult.3 The Hedgehog pathway is responsible for embryonic and fetal development. The product of the PTCH gene is a transmembrane receptor for sonic hedgehog.4 Once the sonic hedgehog binds to PTCH, the intracellular signal transducer SMO will be activated, initiating the downstream signaling events, including GLI1 and SUFU. SUFU is a negative regulator of the Hedgehog signaling pathway.5 Mutation of PTCH1 gene and SUFU gene result in unregulated activation of hedgehog pathway, predisposing to unregulated cell proliferation and apoptosis inhibition. The genetic mutation of Shh group is very similar to that in Gorlin syndrome, which explains why Gorlin syndrome is highly associated with medulloblastoma. It was also found that the Shh subgroup are more likely to experience local recurrence while group 3 and group 4 are prone to metastatic recurrence.6 For the Shh tumours, historically PTeCH1 has been identified as the gene that is causative for medulloblastoma in Gorlin syndrome. It was until 2009 that SUFU, another component of the Shh pathway, was found to be associated with a family of clinically diagnosed Gorlin syndrome with childhood onset of medulloblastoma.7 Such association established genetic heterogeneity of Gorlin syndrome, and increased the chance of molecular diagnosis of Gorlin syndrome.

Medulloblastoma are mostly presumed to be sporadic. Recent research indicates genetic mutations play an important role in causing these rare brain tumours.8 In particular, the molecular subgroup 1 (Wnt) and subgroup 2 (Shh) are highly associated with oncogenes such as TP53, PTCH1, SUFU, BRCA2 and PALB2.8 It was also observed that patients of the Shh subgroup have a high prevalence of damaging germline mutation. Yet, less than half of these patients are suspected to have such mutations based on medical records, leading to delayed or missed diagnosis of cancer predisposing genes and syndromic disorders.8 It is therefore strongly advised that regular genetic counselling and screening shall be provided to these group of patients.

Figure 1 Dermal palmar and plantar skin pits.

Gorlin Syndrome

Gorlin syndrome, also called Nevoid Basal Cell Carcinoma syndrome (NBCCS), is an autosomal dominant disorder that leads to skeletal developmental abnormalities and multi-systemic tumourigenesis.1 The frequency of this disorder ranges from 1/30827 in the UK to 1/238500 in Japan.9,10 Around 1% of patients with Gorlin syndrome develop medulloblastoma usually at the age of 2 to 3 years,9 while basal cell carcinoma and other tumours tend to have age of onset in adolescent or adult.11 Lifelong observation and careful medical attention shall be provided to patients with Gorlin syndrome to monitor the progression of tumours.

First modern literature documented this syndrome was by human geneticist Gorlin in 1960s.12 Basal cell carcinoma, skeletal abnormalities and odontogenic keratocysts (jaw cysts) were the three major findings in his study.12 With recent technological advancement of medical apparatus, pathological skeletal deformation and detection of tumourigenesis can be identified with CT and MRI scans, while molecular diagnosis can be made with specific arrays and Whole Exome Sequencing. Gorlin syndrome can involve congenital abnormalities of multiple systems, while dermatological and skeletal manifestations are reported more often.13 The major criteria for diagnosing Gorlin syndrome includes: (1) Multiple (>2) basal cell carcinomas or one under 30 years, or >10 basal cell naevi. (2) Any odontogenic keratocyst (proven on histology), or polyostotic bone cyst. (3) Palmar or plantar pits (3 or more). (4) Ectopic calcification: lamellar or early (<20 years) falx calcification. (5) Family history of NBCCS. In 1992, the location of gene for Gorlin syndrome is first identified. It was found that the microdeletion of 9q22.3, which includes deletion of PTCH1, is the causative gene of GS.14 In 2002, SUFU mutation is newly identified as a cause of medulloblastoma, which is a loss of function of the tumour suppressor gene. In 2009, a causative link between SUFU mutation and GS through a case report of PTCH1-negative GS family. Current genetic testing for GS include Next Generation Sequencing and Whole Exome Sequencing which covers both PTCH1 and SUFU gene.

In 2017, a publication in the BMJ described the genotype phenotype relationship of Gorlin syndrome.15 Some of the key findings, together with findings from other publications, are tabulated in Table 1.

In retrospect, this patient was presented similarly as the newly-discovered molecular subtype SUFU gene mutation, with higher incidence of childhood medulloblastoma and absence of jaw cysts. The exceptions are that some of the classical presentation of Gorlin syndrome, i.e. macrocephaly and dermal pits on plantar region.

It is important to differentiate PTCH1 and SUFU subgroup of Gorlin syndrome as they have different clinical presentation, recurrence rate and treatment options. The message from this SUFU mutated proband is that SUFU type Gorlin syndrome cause higher incidence and unusual early onset of childhood medulloblastoma. What is more alarming is that SUFU type patients have a higher life risk to develop meningioma or an ovarian fibroma, therefore clinicians are advised to keep a close monitoring of tumour progresses. Moreover, in the Sonic Hedgehog pathway, the G-protein coupled receptor SMO is the key molecule for inhibition. Scientists have discovered SMO-specific targeted drugs such as vismodegib and sonidegib, which has been approved by the FDA for treatment of Basal Cell Carcinoma. Yet, this drug cannot be used on SUFU type Gorlin syndrome. Thus, drugs targeting other signaling molecules like Gli-1, PI3K-mTOR and PKC are under clinical trial. Clinicians should pay attention to the development of the new targeted therapy and which subtypes they are addressed to respectively.

Table 1
  PTCH1 gene mutation SUFU gene mutation
Pathway Sonic Hedgehog Sonic Hedgehog
Rate of medulloblastoma / meningioma Lower Higher
Histopathology of medulloblastoma16 Classical desmoplastic/MBEN
Jaw cysts No Multiple
Risk of Basal Cell Carcinoma in carriers17 Higher Lower
Treatment of SMO inhibition Susceptible Resistant



Gorlin syndrome is a multi-systemic disease that is susceptible to tumourigenesis which require lifelong and careful medical attention from a multidisciplinary team. Infantile and childhood medulloblastoma at the age of onset below six are associated with Gorlin syndrome, while medulloblastoma within the age 6-12 are more likely to be sporadic. It should come to pediatricians' attention that children with early onset of brain tumours could have underlying genetic cause, thus appropriate genetic testing shall be done during or after the course of surgical or medical treatment.


We are thankful to the family for their consent for the publication of their clinical photos.

Declaration of Interest



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