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 Table of Contents  
Year : 2021  |  Volume : 1  |  Issue : 1  |  Page : 29-32

Gorlin syndrome – An adult diagnosis made in childhood

Department of Pediatrics, Associated Kalawati Saran Children's Hospital, Lady Hardinge Medical College, New Delhi, India

Date of Submission02-Oct-2020
Date of Decision25-Oct-2020
Date of Acceptance30-Oct-2020
Date of Web Publication27-Feb-2021

Correspondence Address:
Dr. Sharmila Banerjee Mukherjee
Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi - 110 001
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_7_21

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Background: Syndromes in which some manifestations occur later in life are difficult to diagnose in childhood. A systematic clinical approach may prove to be extremely useful. Gorlin syndrome (GS) is characterized by jaw keratocysts and/or basal cell carcinomas usually appearing in the second decade of life. Clinical Description: A 9-month-old girl, second born to a nonconsanguineous couple, presented with delay in attaining milestones and spinal deformities. There was no significant antenatal, perinatal, neonatal, or family history. She had no neck control, vocalization, or social smile. Fixation and tracking of objects and startle response to sound was present. Salient examination findings were macrocephaly, frontoparietal bossing, flat occiput, hypertelorism, broad nasal bridge, right preauricular pit, palmar pitting, and kyphoscoliosis. X-ray chest revealed bifid vertebra, hemivertebrae, and bifid ribs. Echocardiogram, ultrasound abdomen, magnetic resonance imaging brain, and brainstem-evoked response audiometry were normal. Management: A systematic clinical approach was used that included the following steps: (1) history, examination, and identification of overt anomalies; (2) searching for concealed anomalies; (3) synthesizing information; (4) literature/database search using good search handles; (5) critically analyzing the differential diagnoses; and (6) surveillance for associated morbidities of established diagnosis. We arrived at a clinical diagnosis of GS after applying diagnostic criteria and excluding differential diagnoses. Appropriate intervention was started. The child is under annual follow-up. Conclusion: A systematic clinical approach including an effective search strategy with good handles helps in arriving at a clinical diagnosis in children with dysmorphism.

Keywords: Database search, early diagnosis, systematic clinical approach

How to cite this article:
Mathur SB, Mukherjee SB, Kapoor D, Sharma S. Gorlin syndrome – An adult diagnosis made in childhood. Indian Pediatr Case Rep 2021;1:29-32

How to cite this URL:
Mathur SB, Mukherjee SB, Kapoor D, Sharma S. Gorlin syndrome – An adult diagnosis made in childhood. Indian Pediatr Case Rep [serial online] 2021 [cited 2023 Feb 3];1:29-32. Available from: http://www.ipcares.org/text.asp?2021/1/1/29/310235

Gorlin syndrome (GS) or basal cell nevus syndrome was first described by Gorlin and Goltz in 1960.[1] It is characterized by basal cell carcinomas and jaw keratocysts, which usually appear during or after the second decade of life.[1] Palmar or plantar pits, as well as spine and rib anomalies, are common. Intellectual disability occurs in about 5% of cases.[2] Other neurologic manifestations include ectopic calcifications like that of the falx cerebri, macrocephaly, central nervous system tumors, seizures, congenital hydrocephalus, and Huntington's chorea.

Although clinical and radiologic characteristics have been defined and diagnostic criteria were proposed [Table 1], their sensitivity and specificity are unknown.[3] There is a lot of variability in the clinical phenotype. The heterogeneity of presentation, rarity (estimated prevalence varying from 1 in 57,000 to 1 in 256,000),[2] and late presentation of the characteristic features make it difficult to diagnose GS in children.
Table 1: Diagnostic criteria for Gorlin syndrome*

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We describe a case of GS which was diagnosed in infancy using the systematic clinical approach that is recommended for children with dysmorphism, when the clinical phenotype is not obvious, prima facie. This case report was prepared following the CARE guidelines.[4]

  Clinical Description Top

A 9-month-old girl, second born to a nonconsanguineous couple, presented to our tertiary care hospital with parental concerns regarding developmental delay and deformities of the back. Elicitation of milestones revealed the absence of neck control, vocalization, or social smile. Fixation and tracking of objects was present. Vision and hearing were apparently normal. The antenatal, perinatal, past, or family history was not significant. Anthropometry was normal except a head circumference between +2 and +3 Z-scores. Salient physical examination findings were frontoparietal bossing and a flat occiput, dysmorphic facies with hypertelorism, wide nasal bridge, a right-sided preauricular pit [Figure 1], and kyphoscoliosis. Developmental assessment confirmed delay in gross motor, fine motor, and social and language domains, though the neurological examination was normal, apart from a nonparalytic squint. The rest of the systemic examination was normal.
Figure 1: Frontal profile of our patient at the age of 2.5 years, with macrocephaly, frontoparietal prominence, hypertelorism, and wide nasal bridge

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Since the preliminary clinical phenotype was that of a dysmorphic child with global developmental delay, we proceeded to assess hearing and vision and investigate for overt as well as concealed anomalies. Brainstem-evoked response audiometry revealed normal hearing, and visual assessment found mild hypermetropia and confirmation of the squint. Radiographs and subsequent magnetic resonance imaging (MRI) of the dorsolumbar spine revealed scoliosis of the dorsal spine with hemivertebrae at the level of T3/T4, bifid ribs on the right side (3–6) and on the left side (3–7), and spina bifida at the T2 and T3 levels with expanded and deformed lamina of the T3 and T4 vertebrae. MRI of the brain, echocardiogram, and abdominal ultrasonogram were normal. Addition of these clinical manifestations expanded yet limited the clinical phenotype to “global developmental delay with facial and axial skeletal dysmorphism.”

Management and Outcome

Since the child did not fit into any dysmorphic syndrome known to the treating physicians, a list of all the clinical manifestations was prepared and handles were identified. A literature search was performed using Online Mendelian Inheritance in Man database and the London Dysmorphology Database. Various permutations and combinations were tried, using select handles. The use of the combination of search handles “hypertelorism + bifid ribs + macrocephaly” leads to five differential diagnoses [Figure 2]. The clinical phenotype of each was matched with our patient. The most probable diagnosis appeared to be GS. A focused literature search found consensus criteria that established diagnosis based on (i) one major criterion and molecular confirmation (PTCH 1/2 mutation) or (ii) two major criteria or (iii) one major and two minor criteria [Table 1].[3] In our case, mutation confirmation studies could not be done due to financial constraints. With respect to the six major criteria, palmar pitting was present (becoming evident when the hands were dipped in warm water), basal cell carcinoma and odontogenic cyst were not applicable (late age of presentation), lamellar calcification and medulloblastoma were ruled out by X-ray cranium and MRI, respectively, and one affected family member was uncertain (since we could examine only the parents and sibling). Four minor criteria were present (rib, vertebral, and ocular anomalies plus macrocephaly). After ruling out the other four differentials based on the absence of their salient characteristics [Table 2], we made a final diagnosis of GS.
Figure 2: Screenshot depicting London Dysmorphology Database search strategy with “bifid/fused ribs,” “macrocephaly,” and “hypertelorism.” This leads to five search results

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Table 2: Clinical manifestations of the four differential diagnoses obtained from London Dysmorphology Database search

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The parents and sibling were examined for the major and minor diagnostic criteria of GS, including radiographs of the jaw in the adults. After parental counseling, the patient was started on multidisciplinary early intervention and given practical advice for sun protection (shades and sunscreens) and minimizing ionizing radiation exposure (avoiding radiographs and sharing information with doctors regarding risk). A follow-up surveillance protocol was planned with annual focus on clinical, cardiac, ophthalmological, dermatological, and orodental examinations and assessment of vision, hearing, and developmental status. By the age of 3 years, the behavioral phenotype of autism spectrum disorder (ASD) started to emerge which was confirmed by a comprehensive assessment including the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnostic criteria for ASD. Additional management was initiated. Counseling is repeated annually. The child's weight and height have been between the 50th and 75th percentile curves, but head circumference remained above the 97th percentile till 3 years by the WHO charts. Subsequently, body mass index has been monitored and is within normal range. An ultrasound of the pelvis has been planned when she attains menarche or if symptoms suggestive of an ovarian fibroma (lower abdominal pain and menstrual irregularities) appear. She is currently 8 years old and yet to manifest any of the other features of GS.

  Discussion Top

Pediatricians often encounter children with developmental delay and dysmorphism that do not fit into the mold of the common disorders with familiar clinical phenotypes such as Down syndrome, Fragile X syndrome, or Turner syndrome. A systematic clinical approach should be used in these cases. This stepwise approach includes (1) history taking, detailed examination, and recognition of physical anomalies; (2) searching for concealed anomalies; (3) synthesizing information; (4) literature/database search using good search handles; (5) critically analyzing the differential diagnoses; and (6) surveillance for associated morbidities of the established diagnosis.

The critical step for a meaningful literature search is identification of good search handles. These should be clinical features that are neither very common, so as to be a part of the clinical spectrum of numerous syndromes, nor very rare, so as to be an incidental finding in the clinical spectrum of the actual syndrome. Isolated search handles result in innumerable syndromes being listed, whereas listing multiple features often leads to no syndrome being identified. Various permutations and combinations should be used judiciously. For instance, in our case, the search handles “hypertelorism + bifid ribs” lead to 15 results [Figure 3]. Adding macrocephaly brought it down to five differentials [Figure 2], while using only “bifid/fused” ribs resulted in more than 100 differentials. The next step is to perform a critical appraisal by matching the phenotype of all the differential diagnoses with the prototype and applying the diagnostic criteria (if they exist) followed by the confirmatory test. Following this stepwise approach, we were able to reach to the probable diagnosis, a major challenge being the late presentation of the characteristic features.
Figure 3: Screenshot depicting London Dysmorphology Database search strategy with “bifid/fused ribs” and “hypertelorism.” This leads to 15 search results

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The major clinical features of GS are more commonly seen in adults than children.[5] In a study of 118 cases of GS, <8% were diagnosed in the first decade of their life.[6] Most of these were patients with affected older family members. The earliest a diagnosis is made in new cases is usually in the second decade of life.

There are several genes in the sonic hedgehog (SHH) signaling pathway such as PTCH1, PTCH2, and SUFU.[5] Mutations in the tumor suppressor genes PTCH1 on chromosome 9q22, PTCH2 on chromosome 1p32, or SUFU on chromosome 10q24-q25 have been found to result in GS.[5] PTCH1 is a transmembrane glycoprotein involved in the SHH signaling pathway which plays a role in proper cell fate patterning and growth. In GS, the mutation leading to truncation of the PTCH1 protein is most commonly seen.[5]

Learning, behavioral, or psychiatric problems have been reported previously in GS.[7],[8] Autism has been described in GS earlier in a 9-year-old girl[9] and 5.3-year-old boy.[10] The latter was initially diagnosed with developmental delay at 3.4 years, for which a whole-exome sequence was performed, the PTCH1 mutation was identified, and GS was established after clinical correlation.

Life expectancy in GS is not significantly altered, but there can be substantial morbidity as a result of complications including malignancies and maxillofacial deformities. Early diagnosis is important for counseling of patients to prevent harmful exposure to ultraviolet and ionizing radiations. Retinoids, including isotretinoin, may prevent or slow down the development of new basal cell carcinomas. It is also important not to miss the ocular, skeletal, and facial features of GS in cases presenting with medulloblastomas as radiation therapy may cause basal cell carcinomas in patients with GS.

To conclude, a systematic clinical approach including an effective search strategy using good handles may help in arriving at a clinical diagnosis in children with dysmorphism, especially in syndromes like GS in which some manifestations occur later in life.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the mother has given her consent for images and other clinical information to be reported in the journal. The mother understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Gorlin RJ, Goltz RW. Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome. N Engl J Med 1960;262:908-12.  Back to cited text no. 1
Muzio LL. Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis 2008;3:32.  Back to cited text no. 2
Bree AF, Shah MR; BCNS Colloquium Group. Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS). Am J Med Genet A 2011;155A:2091-7.  Back to cited text no. 3
CARE Case Report Guidelines. Available from: https://www.care-statement.or?g/. [Last accessed on 2020 Sep 20].  Back to cited text no. 4
Akbari M, Chen H, Guo G, et al. Basal cell nevus syndrome (Gorlin syndrome): Genetic insights, diagnostic challenges, and unmet milestones. Pathophysiology 2018;25:77-82.  Back to cited text no. 5
Shanley S, Ratcliffe J, Hockey A, et al. Nevoid basal cell carcinoma syndrome: Review of 118 affected individuals. Am J Med Genet 1994;50:282-90.  Back to cited text no. 6
High A, Zedan W. Basal cell nevus syndrome. Curr Opin Oncol 2005;17:160-6.  Back to cited text no. 7
Díaz-Fernández JM, Infante-Cossío P, Belmonte-Caro R, et al. Basal cell nevus syndrome. Presentation of six cases and literature review. Med Oral Patol Oral Cir Bucal 2005;10 Suppl 1:E57-66.  Back to cited text no. 8
Delbroek H, Steyaert J, Legius E. An 8.9 year old girl with autism and Gorlin syndrome. Eur J Paediatr Neurol 2011;15:268-70.  Back to cited text no. 9
Llerena JC, Esposito AC, Serao C, et al. Further example of classical autism patient associated to PTCH1 Gorlin syndrome. JSM Commun Dis 2018;2:1009.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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