Genetic skin disorders: The value of a multidisciplinary clinic

Abstract

Genodermatoses are inherited disorders with skin manifestations and can present with multisystem involvement, resulting in challenges in diagnosis and treatment. To address this, the expertise of dermatology and clinical genetics through a multidisciplinary clinic (Genodermatoses Clinic) were combined. A retrospective cohort study of 45 children seen between March 2018 and February 2019 in the Genodermatoses Clinic at The Children’s Hospital of Philadelphia was performed. Patient demographics, referral information, genetic testing modality, diagnoses, and patient satisfaction scores were evaluated to assess the clinic’s impact. The majority of patients (42.2%) were referred from Dermatology and 86.7% were referred for diagnosis. Two-thirds of the patients were recommended genetic testing, and subsequently 73.3% completed testing. Nearly three-quarters, 26 out of 36 patients (72.2%), of our undiagnosed patients received a clinical and/or molecular diagnosis, which is imperative in managing their care. Twenty-two individuals pursued genetic testing. In eight individuals (36%), molecular testing was diagnostic. However, in two individuals the molecular diagnosis did not completely explain the phenotype. However, there are still obstacles to genetic testing, such as cost of testing and insurance barriers. Almost all (91.4%) rated the Genodermatoses Clinic as “Very Good,” the top Press Ganey score. High patient satisfaction scores suggest a positive impact of the Genodermatoses clinic, emphasizing the importance to increase support for the clinical and administrative time needed for patients with genodermatoses.

1 |. INTRODUCTION

As the selection of genetic testing modalities becomes increasingly accessible and affordable, physicians across nearly all specialties have struggled with how to properly and effectively incorporate these new technologies into their practices. Previous studies have shown demonstrable clinical benefit to genetic diagnosis across multiple medical specialties, especially in diagnosis of rare genetic diseases (Boycott et al., 2017). However, a paucity of data exists regarding the application of such testing in genetic skin disorders, despite the progress in recent years characterizing the molecular etiology of genodermatoses. Genodermatoses are genetic skin disorders that may have additional manifestations in other organ systems. They encompass about 400 disorders and are subdivided into phenotypic categories such as blistering disorders, abnormal cornification, pigmentation disorders, epidermal nevus syndromes, hair disorders, ectodermal dysplasias, connective tissue disorders, vascular disorders, and syndromes associated with tumor predisposition (Schaffer, 2016).

This progress in elucidating the underlying pathology of these diseases has transformed the clinical concept of genodermatoses from a limited set of familial syndromes based solely on similarity of clinical phenotype to broader pathway families (Schaffer, 2016). Identification of a molecular etiology can provide insight into the patient’s disease such as other clinical manifestations and prognosis as well as recurrence risk (Tantcheva-Poór, Oji, & Has, 2016). Despite advances in knowledge and reasons for testing, remaining clinical and research challenges include accurate diagnosis, clinical care recommendations, elucidation of underlying molecular pathways, and therapeutic development due to the nature of these ultra-rare disorders (Austin et al., 2018).

Pediatric patients with genetic skin disorders may first present to a dermatologist due to physical symptoms. Shagalov et al. illustrated that nearly all practicing pediatric dermatologists care for patients requiring genetic analysis, but that due to poor rates of insurance coverage, the number of patients completing testing is quite low (Shagalov, Ferzli, Wildman, & Glick, 2017). Additionally, practicing dermatologists in the community may not regularly see patients with these rare syndromes. Ordering the appropriate genetic testing can be challenging and moreover many dermatologists do not have the training for interpreting genetic testing. On the other hand, dermatology is helpful for precise identification of skin lesions. Without this information, the geneticist may send unnecessary testing and thus inflate health care costs and potential caregiver anxiety. This high level of demand for genetic data combined with the low rate of utilization highlights the need for further exploration into the potential clinical utility of combining the expertise of medical geneticists and the practice of pediatric dermatology.

We addressed this need by evaluating the multidisciplinary Genodermatoses Clinic over the course of a year, with care provided by a clinical geneticist, genetic counselor, and dermatologist simultaneously. Many combined clinics exist similar to this throughout the country, but little has been reported about the utility of this approach. There are several multidisciplinary clinics in the field of dermatology that have been reported such as a psychodermatology clinic and a combined rheumatology and dermatology clinic (Zhou, Mukovozov, & Chan, 2018) (Samycia, McCourt, Shojania, & Au, 2016). There are also several multidisciplinary clinics in the field of genetics that have been reported such as a neurogenetics clinic (Bardakjian et al., 2018). However, there is limited data on a combined genetics and dermatology clinic. Here we add to the scarce literature by presenting the experiences of such a multidisciplinary genodermatoses clinic, including the diagnoses seen in this clinic and discuss the benefits and limitations.

2 |. METHODS

To evaluate the impact of a combined clinic, we performed a retrospective cohort analysis on 45 patients seen in the multidisciplinary monthly Genodermatoses Clinic at the Children’s Hospital of Philadelphia (CHOP) from March 2018 to February 2019. This study is covered under IRB 19–016769 (Genetic Skin Disease Registry). Patients were simultaneously evaluated by a board-certified geneticist, licensed genetic counselor, and board-certified pediatric dermatologist in a collaborative clinic between the Section of Dermatology and Division of Human Genetics, both under the larger umbrella of the Department of Pediatrics. Both specialists bill insurance individually. The clinic is held in Dermatology space for access to larger procedure room and other supplies if necessary for assessment. This clinical evaluation included medical history; developmental history; family medical history, including ethnicity and consanguinity; and physical examination to document measurements, dysmorphic features, hair, skin, teeth, nail differences, and examination of sweating if relevant. Previous medical records, laboratory, imaging, pathology, and genetic testing were reviewed if available. Laboratory and genetic testing, imaging studies, skin biopsy, and clinical referrals were performed if clinically indicated. Genetic studies were performed at a clinical testing laboratory with pathogenicity classification by American College of Medical Genetics and Genomics guidelines unless otherwise specified (Table 3) (Richards et al., 2015). Press Ganey scores, which are selfreported patient satisfaction scores, were assessed from the Genodermatoses Clinic, Division of Genetics and Section of Dermatology at CHOP (Press Ganey Corporation, 2020). Press Ganey scores ranged from Very Good, Good, Fair, Poor to Very Poor. Demographic characteristics of patients are shown in Table 1.

TABLE 3.

Clinical and/or molecular information for individuals seen in the clinic

Referred for diagnosis, genetic testing recommended and completed, clinical and molecular diagnosis (8)
Clinical diagnoses/phenotype	Gene or copy number variant	Coding sequence; protein variant	Zygosity	ACMG pathogenicity call	Inheritance if known	Type of genetic test performed to obtain result	Laboratory testing performed	Additional comments
Hypohidrotic ectodermal dysplasia	NM_001399.4 EDA NM_025216.2 WNT10A	c.929A>G; p.Y310C c.682T>A; p.F228I	Hemizygous Heterozygous	Likely pathogenic Pathogenic	Maternally inherited Maternally inherited (mother affected)	Gene panel, SNP microarray	Gene DX, CHOP DGD	EDA variant classified by GeneDX as pathogenic; our classification is likely pathogenic
Ichthyosis vulgaris, developmental delay, submucous cleft palate, cryptorchidism	NM_002016.1 FLG	c.1501C>T; p.r501* c.2282_2285del4; p.S761Cfs*36	Heterozygous Heterozygous	Pathogenic Pathogenic	Paternally inherited Maternally inherited	Karyotype, exome sequencing	CHOP DGD	FLG only explains skin manifestations
Nevus comedonicus syndrome	NM_033116.5 NEK9	c.1755_1757del; p.T586del	(mean allele frequency 28%, nevus)	Likely pathogenic	NA	Single gene testing	Prevention genetics
PIK3CA-related Overgrowth Spectrum	NM_006218.2 PIK3CA	c.1624G>A; p.E542K	“Allele frequency consistent with somatic origin” from epidermal nevus, absent from blood	Pathogenic	NA	Gene panel and single gene (sent simultaneously)	GPS at WUSTL
Blue rubber bleb nevus syndrome	NM_000459.3 TEK	c.2744G>A; p.R915H	Heterozygous	Pathogenic	Parents not interested	Gene panel	CTGT
Capillary malformation arteriovenous malformation syndrome	NM_002890.2 RASA1	c.1659C>A; p. Y553*	Heterozygous		Unknown (assumed paternal based on family history)	Gene panel	UAB
Xeroderma pigmentosum type C	NM_004628.4 XPC	c.420_423del; p.E141Lfs*6 c.1677C>A; p.Y559*	Heterozygous Heterozygous	Pathogenic Likely pathogenic	Maternal Paternal	Gene panel	Prevention genetics
TANC2 related neurodevelopmental disorder and mastocytosis	NM_025185.3 TANC2	c.4955_4967delGAGTCAG CCAGAG; p.G1652Afs*13	Heterozygous	Likely pathogenic	Suspected maternal mosaic	Exome sequencing	CHOP DGD	TANC2 only explains neurodevelopmental issues and not the mastocystosis
Referred for diagnosis, genetic testing recommended and completed, clinical diagnosis only (8)
Clinical diagnoses/phenotype	Gene or copy number variant	Coding sequence, variant	Zygosity	ACMG pathogenicity call	Inheritance if known	Type of genetic test performed to obtain result	Laboratory testing performed	Additional comments
Piebaldism	NM_000222.2 KIT	c.2468A>G; p.Y823C	Heterozygous	VUS	Unknown	Gene panel	Gene DX
Palmoplantar keratoderma	NM_006121.3 KRT1	c_723_740del; p.R241_K246del	Heterozygous	VUS	Maternally inherited (mother affected)	Gene panel; exome sequencing	Gene DX
Thyroxine-binding globulin deficiency with alopecia universalis	NM_000354.5 SERPINA7	c.1234C>G; p.P412A	Heterozygous	VUS	Paternally inherited	Single gene, SNP microarray, exome sequencing	CHOP DGD	Patient was known to have low thyroxine-binding globulin levels at the time of evaluation.
Hypohidrotic ectodermal dysplasia	NM_145861.2 EDARADD	c.392C>T; p.P131L	Homozygous	VUS	Pending	Gene panel, SNP microarray	Invitae, CHOP DGD
In utero drug exposure	NA							Noonan syndrome gene panel negative
Blue rubber bleb nevus syndrome	NA							TEK, GLMN sequencing and deletion duplication testing from blood and lesion negative
Ectodermal dysplasia (2)	NA					Ectodermal dysplasia gene panel	Invitae	Negative
Referred for diagnosis, genetic testing recommended and completed, no diagnosis (6)
Clinical diagnoses/phenotype	Gene or copy number variant	Coding sequence, variant	Zygosity	ACMG pathogenicity call	Inheritance if known	Type of genetic test performed to obtain result	Laboratory testing performed	Additional comments
Ichthyosis vulgaris	NM_002016.1 FLG	c.9793G>A; p.G3265R	Heterozygous	Likely benign	Maternally inherited	Chromosome breakage studies, SNP microarray, exome sequencing	Cincinatti Children’s, CHOP DGD	FLG variant classified as VUS by CHOP DGD, our classification is likely benign
Developmental delay and mastocytosis	NA							Negative SNP microarray, fragile X, quintet exome with sister as proband
Developmental delay and mastocytosis	NA							Negative quintet exome with sister as proband
Expressive language delay, motor delay, multiple hemangiomas, connective tissue nevi, cor triatriatum, and aberrant right subclavian artery	NM_006364.3 SEC23A NM_001266856 GNA11	c.560A>G; p.Y187C c.230A>G; p.K77R	Heterozygous Heterozygous	VUS VUS	Maternally inherited Paternally inherited	SNP microarray, trio exome sequencing, somatic overgrowth panel	CHOP DGD, Penn GDL	SEC23A deletion/duplication testing to GeneDX negative
Developmental delay and xerosis	NA					SNP microarray, fragile X	CHOP DGD	Negative
Atopic dermatis and congenital anomaly of the kidney and urinary tract	NM_000296 PKD1	c.776G>A; p.C259Y	Heterozygous	Likely pathogenic	Unknown	Kidney-seq	IIHG	14 additional VUSes; Awaiting authorization for exome sequencing
Referred for diagnosis, genetic testing recommended but not completed (4)
Clinical diagnoses/phenotype	Gene or copy number variant	Coding sequence, variant	Zygosity	ACMG pathogenicity call	Inheritance if known	Type of genetic test performed to obtain result	Laboratory testing performed	Additional comments
X-linked ichthyosis	NA							Parents declined
Multiple capillary Malformations	NA							Teseting not approved by insurance
Common variable immunodeficiency, telangiectasias, renal hypoplasia	NA							Out of pocket cost too high to proceed with testing
Familial hyperpigmentation with or without hypopigmentation	NA							Parents interested in testing, not approved by insurance
Referred for diagnosis, no genetic testing recommended (10)
Clinical diagnoses/phenotype	Gene or copy number variant	Coding sequence, variant	Zygosity	ACMG pathogenicity call	Inheritance if known	Type of genetic test performed to obtain result	Laboratory testing performed	Additional comments
Isolated port wine stain	NA
Pseudoxanthoma elasticum	NA							Opted for testing at specialty clinic
Atopic dermatitis (3)	NA
Ichthyosis vulgaris	NA
Benign pigmentary mosaicism (2)	NA
Familial hyperpigmentation with or without hypopigmentation	NA
Premature graying of hair, progressive areas of hyperpigmentation, developmental delay	NA							Testing sent at outside institution
Referred for counseling and diagnosis (4)
Clinical diagnoses/phenotype	Gene or copy number variant	Coding sequence, variant	Zygosity	ACMG pathogenicity call	Inheritance if known	Type of genetic test performed to obtain result	Laboratory testing performed	Additional comments
Oculocutaneous albinism	NM_000275.2 OCA2	c.819_822delinsGGTC; p.N273_W274delinsKV c.1699G>A; p.E567K	Unknown	Pathogenic VUS	Unknown	Gene panel, enzyme testing	Denver genetics	No pathogenicity calls or NM transcript number; performed in 2011
Idiopathic infantile hypercalcemia and epidermal inclusion cysts (2, siblings)	NM_000782.4 CYP24A1	c.428_430delAAG; p.E143del c.1186C>T; p.R396W	Compound heterozygous	Pathogenic (previously reported)	Maternal, paternal	Research quad exome	Dupont
Sturge–Weber syndrome	NA	NA	NA	NA	NA	NA	NA
Referred for counseling (5)
Clinical diagnoses/phenotype	Gene or copy number variant	Coding sequence, variant	Zygosity	ACMG pathogenicity call	Inheritance if known	Type of genetic test performed to obtain result	Laboratory testing performed	Additional comments
Hermansky–Pudlak syndrome type 3	NM_032383.4 HPS3	c.−2874_217 + 673del	Homozygous	Pathogenic	Maternal, paternal	Gene panel; SNP microarray	Molecular vision laboratoryArray: CHOP DGD
Patau syndrome with severe acne	mos 47,XY,+13[18]/46,XY[2]	NA	NA	NA	NA	Karyotype	Jefferson
Gorlin syndrome	arr[hg19] 9q22.2q22.33 (93,745,280–100,395,565)x1	NA	NA	NA	NA	Microarray	Quest
Tuberous sclerosis 2	NM_000548.3 TSC2	c.2194C>T; p.Q732*	Heterozygous	Pathogenic	Unknown	Gene panel	Athena (performed in 2006)
Keratitis–ichthyosis–deafness syndrome	NM_004004.5 GJB2	c.148G>A; p.D50N	Heterozygous	Pathogenic	de novo	Single gene	CHOP DGD

Abbreviations: CHOP DGD, The Children’s Hospital of Philadelphia Division of Genomic Diagnostics; GPS at WUSTL, Genomic and Pathology Services at Washington University in St. Louis; CTGT, connective tissue gene tests; UAB, University of Alabama; Penn GDL, University of Pennsylvania Genetic Diagnostic Laboratory; IIHG, Iowa Institute of Human Genetics.

TABLE 1.

Cohort demographics

Demographic	Percentage
Male	55.6% (n = 25)
Female	44.4% (n = 20)
Caucasian	57.8% (n = 26)
African American	17.8% (n = 8)
Asian	0
Hispanic	8.9% (n = 4)
Pacific islander	0
Mixed ethnicity	11.1% (n = 5)
“Other”	4.4% (n = 2)
Infant (<2)	44.4% (n = 20)
Toddler (2–4)	20.0% (n = 9)
School aged (5–12)	26.7% (n = 12)
Adolescent (13–18)	8.9% (n = 4)
Residence <50 miles from clinic	55.6% (n = 25)
Residence 50–100 miles from clinic	33.3% (n = 15)
Residence >100 miles from clinic	11.1% (n = 5)

3 |. RESULTS

3.1 |. Demographics

A total of 45 patients were evaluated in the first 12 months of the Genodermatoses Clinic (Table 1). There was a slight male predominance. The majority of patients were self-described Caucasian, followed by African American. The predominant age group seen was less than 2 years old. The majority of the patients traveled from less than 50 miles away, however, five patients traveled from more than 100 miles to attend our clinic. Of the 45 patients evaluated in the clinic, about three-quarters had a genodermatosis suspected after evaluation.

3.2 |. Referrals

Forty-five patients were referred to the clinic (Table 2). Dermatology was the largest referral source. The majority of patients were referred for diagnosis including two patients referred for a second opinion (Table 2). About one quarter of individuals were referred for a congenital anomaly(ies) plus skin manifestation. This was the main referral reason.

TABLE 2.

Referral information

Referral information	Percentage
Referral source
Plastic surgeons	4.4% (n = 2)
Genetics	4.4% (n = 2)
Self	6.7% (n = 3)
Neurology	4.4% (n = 2)
Nephrology	6.7% (n = 3)
General pediatrics	24.4% (n = 11)
Inpatient	4.4% (n = 2)
Urology	2.2% (n = 1)
Dermatology	42.2% (n = 19)
Referral indication
Diagnosis	82.2% (n = 37)
Counseling	13.3% (n = 6)
Second opinion	4.4% (n = 2)
Referral category
Developmental delay plus skin manifestation	15.6% (n = 7)
Congenital anomaly(ies) plus skin manifestation	24.4% (n = 11)
Vascular disorders	13.3% (n = 6)
Disorders of ectodermal appendages	8.9% (n = 4)
Connective tissue disorder	2.2% (n = 1)
Disorders associated with malignancy	8.9% (n = 4)
Pigmentation disorder	15.6% (n = 7)
Keratinization disorder	11.1% (n = 5)

Note: Specialties that have referred individuals to the clinic. Referral indication for the individuals seen in the clinic. Category of disorder suspected by the referring physician.

3.3 |. Genetic testing

Genetic testing for molecular diagnosis was recommended in two-thirds (n = 30) of patients (Table 3). There were multiple reasons patients did not have genetic testing recommended. Five patients were seen in the clinic for counseling regarding a known diagnosis, one was referred to a specialty clinic for Pseudoxanthoma Elasticum (PXE) and elected to have testing performed there, and one had testing pending at outside institution (n = 1). There were eight patients where the Genodermatoses Clinic’s physicians were able to provide clinical diagnoses and did not recommend genetic testing.

Of the 30 patients in whom further workup was recommended, 26 patients (86.7%) were referred for diagnosis and 4 patients (13.3%) were referred for diagnosis along with counseling. Eight (26.7%) patients did not complete all recommended testing. For six patients, insurance denied coverage or the out of pocket cost to the family was cost-prohibitive. In one case, the parents declined testing. Another patient did not complete testing as it would not significantly change medical management and it would be hard to complete skin biopsy without sedation. Out of pocket costs ranged from $200.00 to $25,561.86. Of the 22 patients who completed further workup, 8 patients (36.4%) received a molecular diagnosis, 8 patients (36.4%) received a clinical diagnosis, 6 patients (27.2%) did not receive a clinical or molecular diagnosis. Skin disease varied greatly and the same genodermatosis was rarely seen twice in those referred for diagnosis (Table 3).

3.4 |. Patient satisfaction scores

We evaluated the patient satisfaction scores for the patients seen in the clinic. Top box score (TBS) is the percent of all answered questions that received a “Very Good” response. Each answered question has equal weight in the final score. Almost all (91.4%) of patients from the first 12 genodermatoses clinics scored the clinic in the TBS for patient satisfaction scores (Press Ganey scores). This was higher than the percentage of patients that scored Dermatology clinic or Genetics clinic in the top box (83.6 and 82.2%, respectively) during the same March 2018 to February 2019 time frame. For the overall assessment of the Genodermatoses clinic, 100% of patients rated care received during visit, staff working together and likelihood of recommending as all “Very Good.”

4 |. DISCUSSION

In this retrospective cohort study, we evaluated 45 patients in the CHOP Genodermatoses Clinic. After this initial feasibility period, we now evaluate 6–8 patients per clinic. The majority of patients (91.1%) were ages 12 and under, with 44.4% presenting under the age of 2. This is consistent with the fact that most genodermatoses present with early signs on the skin (Shagalov et al., 2017). Early overarching genetic diagnosis can aid in the child’s development and in assessing other organ systems in a prompt manner (Laimer, Bauer, & Lang, 2015).

The majority of patients seen in this clinic (55.6%) lived within 50 miles of the Children’s Hospital of Philadelphia and all but five lived within 100 miles of our location. Combined dermatologygenetics practices are rare even at large academic medical centers. Ours is one of only six specialty genodermatoses clinics in eastern North America and yet was able to be filled almost exclusively with patients from nearby areas. This, coupled with the paucity of other such specialized clinics across the country suggests that streamlined, multispecialty care of genetic skin diseases may be unavailable to patients throughout a large portion of the United States and evinces the need for continued exploration into how to address this unmet need. On the other hand, five patients (11.1%) traveled a distance greater than 100 miles to the multidisciplinary clinic (106, 157, 190, 254, and 308 miles). This indicates that families see the necessity and place value on this type of multidisciplinary care.

The single largest source of referrals to this clinic was Dermatology. General pediatrics (24%) was the only other specialty that referred more than three patients. This both emphasizes both the tertiary nature of a genodermatoses clinic and highlights the unique clinical skill sets needed to best care for these patients and to refer patients for testing. The number of referrals from other pediatric dermatologists emphasizes the importance of a specialized clinic for the care of genetic skin disease. Reasons cited for these dermatologists having their patients seek additional specialized care included the large investment of time out of a busy clinic needed for proper evaluation, counseling, and full consideration of the genetic testing options as well as specific expertise and comfort with certain disorders.

A continued barrier to multispecialty clinics involving genetics is the time-consuming process for obtaining coverage and coordinating genetic testing, which can take a few weeks to several months (Lister Hill National Center for Biomedical Communications, 2019). Of the 22 who completed genetic testing at our facility, 1 patient is still awaiting authorization for additional testing. Setbacks in obtaining and receiving results from genetic testing may cause unnecessary delays in patient care. Out-of-pocket costs for genetic testing continue to be a barrier in patient care, as well (Silverman, 2004). In our patient population, out-of-pocket costs ranged from $200.00 to $25,561.86 and 6 out of 30 patients (20%) did not complete testing due to insurance denial or out-of-pocket costs. The outcomes from this quality improvement project add to the evidence that timely and costefficient genetic testing is valuable in improving diagnosis and treatment of children with rare genetic diseases (Marshall et al., 2019). Furthermore, this serves as an indication to improve reimbursement for genetic testing by insurance payers.

Many multidisciplinary groups struggle with space and billing issues. We have not had these issues due to smaller size of the group and support from respective departments. Families are notified they are seeing two specialists in single space and shared time. Families are also made aware they may be responsible for two co-pays. In our experience, reimbursement has not been an issue for either provider as both provide documentation and bill. However, only one provider can bill on time spent and the other must bill on the elements in the note.

The higher TBS score (91.4%) seen in the combined clinic compared with the separate Dermatology (83.6%) and Genetics clinics (82.2%) highlights that patients valued the efforts and services of the multidisciplinary Genodermatoses clinic. Written comments from the Press Ganey scores applauded time spent with patients, time taken to answer questions, preparation for the visit, help coordinating with insurance for genetic testing and overall teamwork environment between dermatology and genetics. This suggests that patients with genodermatoses may have a more positive experience from a combined clinic, rather than seeing Dermatology and Genetics separately.

In order to validate the continual need for a combined, multispecialty clinic to care for these patients, we wanted to determine what proportion of patients who were referred to the clinic ultimately needed the combined expertise of all team members. Among patients referred for diagnostic purposes only (n = 36), we found that nearly three-quarters (n = 26, 72.2%) received a clinical or molecular diagnosis. This creates a “specificity” value that states that referrals to this Genodermatoses clinic accurately predicted the need for further evaluation and genetic testing. Referring dermatologists appear to be largely capable of identifying cutaneous disease that is consistent with a possible genetic etiology, but—as stated above—for various reasons lack the time, confidence or capabilities to fully manage these diseases. This may be due to the suspected syndromic nature of the diseases referred to the clinic, as 40% of patients had a skin manifestation plus either developmental delay or congenital anomaly. On the other hand, there were three patients with atopic dermatitis who had been referred for ichthyosis. These findings strongly suggest the need for a singular clinic with both in-house geneticists and dermatologists because all but a small number of diagnostic patients require the coordinated efforts and expertise of the entire multispecialty team.

Due to the combined expertise, we recommended gene panels prior to exome sequencing. Panels have a faster turnaround time and are more likely to be covered by insurance. Interestingly 6 of the 8 (75%) patients received a diagnosis from targeted or panel testing. The other two patients received a diagnosis from exome sequencing, though these diagnoses did not completely explain all aspects of the patient phenotypes. This emphasizes the diagnostic capabilities of both genetics and dermatology as a team as patients seek a diagnosis.

A previously published case from our cohort demonstrates the need for multidisciplinary care (Sheppard et al., 2020). The patient was cared for in the neonatal intensive care unit for a large congenital pulmonary airway malformation (CPAM) of the lung. Genetic and Dermatology evaluations were inconclusive at that time. He then presented to dermatology with widespread patches of open comedones and mild hypopigmentation. He was referred to the Genodermatoses Clinic by the dermatologist. After evaluation, patient was found to have delayed fine motor and language development, and a causative variant in NEK9 was discovered in the affected skin. Following careful review of this patient, providers in the Genodermatoses Clinic recommended brain MRI due to the structural brain differences associated with nevus comedonicus syndrome. Brain MRI results showed a 10 mm aneurysm and several brain anomalies. CPAM has never been reported in association with nevus comedonicus, but providers at the Genodermatoses Clinic suspect this may be an expansion of the phenotype of this syndrome. The novel finding adds to the care of patients with nevus comedonicus syndrome, as it suggests MR angiogram should be considered when imaging for structural brain malformations. Overall, this multifaceted case emphasizes the value of a combined clinic, especially in diagnosing and managing disorders that present with various symptoms and phenotypes that need attention from numerous specialties.

Overall, the experiences and results of this clinic serve as a strong affirmation of the need for combined multispecialty care of genetic skin disease. These findings demonstrate a continual need for research and funding aimed at increasing access to streamlined care for this group of rare but important diseases. While there are still many obstacles to diagnosing and treating these diseases, we are optimistic that there is great potential for progress in providing comprehensive care to patients with genodermatoses in the coming years.

DATA AVAILABILITY STATEMENT

Information was abstracted from the Genodermatoses Clinical Registry that is IRB approved by the Childrens Hospital of Philadelphia (IRB 19–01676). Thus, additional data are not publicly available due to privacy or ethical restrictions.