In many patients, symptoms are present for a considerable time before diagnosis. The most common clinical features of IPF include the following:

- Age over 50 years

- Dry, non-productive cough on exertion

- Progressive exertional dyspnea (shortness of breath with exercise)

- Dry, inspiratory bibasilar "velcro-like" crackles on auscultation (a crackling sound in the lungs during inhalation similar to Velcro being torn apart slowly, heard with a stethoscope).

- Clubbing of the digits, a disfigurement of the finger tips or toes (see image)

- Abnormal pulmonary function test results, with evidence of restriction and impaired gas exchange.

Some of these features are due to chronic hypoxemia (oxygen deficiency in the blood), are not specific for IPF, and can occur in other pulmonary disorders. IPF should be considered in all patients with unexplained chronic exertional dyspnea who present with cough, inspiratory bibasilar crackles, or finger clubbing.

Assessment of "velcro" crackles on lung auscultation is a practical way to improve the earlier diagnosis of IPF. Fine crackles are easily recognized by clinicians and are characteristic of IPF.

If bilateral fine crackles are present throughout the inspiratory time and are persisting after several deep breaths, and if remaining present on several occasions several weeks apart in a subject aged ≥60 years, this should raise the suspicion of IPF and lead to consideration of an HRCT scan of the chest which is more sensitive than a chest X-ray. As crackles are not specific for IPF, they must prompt a thorough diagnostic process.

Pulmonary Langerhans cell histiocytosis, silicosis, coal workers pneumoconiosis, carmustine related pulmonary fibrosis, respiratory broncholitis associated with interstitial lung disease.

- Lower lung predominance

Idiopathic pulmonary fibrosis, pulmonary fibrosis associated with connective tissue diseases, asbestosis, chronic aspiration

- Central predominance (perihilar)

Sarcoidosis, berylliosis

- Peripheral predominance

Idiopathic pulmonary fibrosis, chronic eosinophilic pneumonia, cryptogenic organizing pneumonia

Pulmonary edema, connective tissue diseases, asbestosis, lymphangitic carcinomatosis, lymphoma, lymphangioleiomyomatosis, drug-induced lung diseases

- Lymphadenopathy

Sarcoidosis, silicosis, berylliosis, lymphangitic carcinomatosis, lymphoma, lymphocytic interstitial pneumonia

Idiopathic pulmonary fibrosis (IPF) is a chronic irreversible and ultimately fatal disease characterized by a progressive decline in lung function. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This official statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was approved by the ATS board of directors, June 2013 and by the ERS Steering Committee, March 2013. "Am Respir Crit Care Med." 188 (6): 733–748. September 15, 2013. The term pulmonary fibrosis means scarring of lung tissue and is the cause of worsening dyspnea (shortness of breath). Fibrosis is usually associated with a poor prognosis.

IPF belongs to a large group of more than 200 lung diseases known as interstitial lung diseases (ILDs), characterized by the involvement of lung interstitium. The interstitium, the tissue between the air sacs in the lung, is the primary site of injury in ILDs. However, these disorders frequently affect not only the interstitium, but also the airspaces, peripheral airways, and vessels. Lung tissue from people with IPF shows a characteristic histopathologic pattern known as usual interstitial pneumonia (UIP). UIP is therefore the pathologic counterpart of IPF. The term 'idiopathic' is used because the cause of pulmonary fibrosis is still unknown. IPF usually occurs in adults of between 50 and 70 years of age, particularly those with a history of cigarette smoking, and affects more men than women. The diagnosis of IPF requires exclusion of other known causes of ILDs and the presence of a typical radiological pattern identified through high resolution computed tomography (HRCT). In the right clinical setting, it is possible to make the diagnosis of IPF by HRCT alone, obviating the need for surgical lung biopsy.

Treatment to slow down the progression of the disease may include nintedanib or pirfenidone.

Most common:

- Chest Pain

- Cough

- Fever

- Shortness of breath

- Joint pain, stiffness, swelling

- Skin nodules

People may not present with all these symptoms or non at all.

From most to lest common:

- Pleural involvement (pleurisy, effusions)

- Pulmonary parenchymal nodules, more common in men than in women

- Rheumatoid-associated interstitial lung disease

- Bronchiolitis obliterans organizing pneumonia

- Obliterative bronchiolitis (obstructive lung disease/bronchiectasis)

- Rheumatoid-associated pulmonary hypertension

- Pulmonary vasculitis/arteritis

- Shrinking lung syndrome

- Miscellaneous: MTX, cricoarytenoid arthritis, infection, cancer

Initially symptoms asymptomatic or some patients do not experience symptoms at all. In a progressive TBM case symptoms include:

- shortness of breath

- a cough

- mucus build up

- wheezing

- difficulty in breathing

- bluish coloration to skin around the nose and mouth

Symptoms may become worse if the patient is stressed, sick, lying down, or forcing a cough.

- Chronic cough

Tracheobronchomalacia or TBM is a condition characterized by flaccidity of the tracheal support cartilage which leads to tracheal collapse. This condition can also affect the bronchi. There are two forms of this rare condition: primary TB and secondary TB. Primary TB is congenital and starts as early as two years old. It is mainly linked to genetic causes. Secondary TB is acquired and starts in adulthood. It is mainly developed after an accident or chronic inflammation.

On 28 May 2013, it was reported that a cure had been developed via a 3D printed windpipe. This cure has currently saved the lives of at least 3 infants.

Atypical infections are the key clinical manifestation of SGD. Within the first few years of life, patients will experience repeated pyogenic infections by species such as "Staphylococcus aureus", "Pseudomonas aeruginosa" or other Enterobacteriaceae, and "Candida albicans". Cutaneous ulcers or abscesses and pneumonia and chronic lung disease are common. Patients may also develop sepsis, mastoiditis, otitis media, and lymphadenopathy. Infants may present with vomiting, diarrhea, and failure to thrive.

Diagnosis can be made based upon CEBPE gene mutation or a pathognomonic finding of a blood smear showing lack of specific granules. Neutrophils and eosinophils will contain hyposegmented nuclei (a pseudo-Pelger–Huet anomaly).

LRBA deficiency presents as a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. Predominant clinical problems include idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), and an autoimmune enteropathy. Before the discovery of these gene mutations, patients were diagnosed with common variable immune deficiency (CVID), which is characterized by low antibody levels and recurrent infections. Infections mostly affect the respiratory tract, as many patients suffer from chronic lung disease, pneumonias, and bronchiectasis. Lymphocytic interstitial lung disease (ILD) is also observed, which complicates breathing and leads to impairment of lung function and mortality. Infections can also occur at other sites, such as the eyes, skin and gastrointestinal tract. Many patients suffer from chronic diarrhea and inflammatory bowel disease. Other clinical features can include hepatosplenomegaly, reoccurring warts, growth retardation, allergic dermatitis, and arthritis. Notably, LRBA deficiency has also been associated with type 1 diabetes mellitus. There is significant clinical phenotypic overlap with disease caused by CTLA4 haploinsufficiency. Since LRBA loss results in a loss of CTLA4 protein, the immune dysregulation syndrome of LRBA deficient patients can be attributed to the secondary loss of CTLA4. Because the predominant features of the disease include autoantibody-mediated disease (AIHA, ITP), Treg defects (resembling those found in CTLA4 haploinsufficient patients), autoimmune infiltration (of non-lymphoid organs, also resembling that found in CTLA4 haploinsufficient patients), and enteropathy, the disease has been termed LATAIE for LRBA deficiency with autoantibodies, Treg defects, autoimmune infiltration, and enteropathy.

Neutrophil-specific granule deficiency (SGD, previously known as lactoferrin deficiency) is a rare congenital immunodeficiency characterized by an increased risk for pyogenic infections due to defective production of specific granules and gelatinase granules in patient neutrophils.

LRBA deficiency is a rare genetic disorder of the immune system. This disorder is caused by a mutation in the gene "LRBA". LRBA stands for “Lipopolysaccharide (LPS)-responsive vesicle trafficking, beach- and anchor-containing” gene. This condition is characterized by autoimmunity, lymphoproliferation, and immune deficiency. It was first described by Gabriela Lopez-Herrera from University College London in 2012. Investigators in the laboratory of Dr. Michael Lenardo at National Institute of Allergy and Infectious Diseases, the National Institutes of Health and Dr. Michael Jordan at Cincinnati Children’s Hospital Medical Center later described this condition and therapy in 2015.

At birth, there is no sign that a child will develop symptoms of aspartylglucosaminuria. Typically, signs and symptoms become apparent between two and four years of age and become progressively worse as the individual ages. The following signs and symptoms may appear:

- Individuals are more prone to respiratory infections

- Development of scoliosis

- Seizures or difficulty with movement

- Skin and joints may become loose

- Facial features change progressively; this may include:

- Progression of developmental and mental disabilities, including:

- An intellectual peak occurs in the mid-teens and allows a plateau for the disease. Once an individual hits the age of 25-30 the decrease begins again, including:

(Children are physically uncoordinated, but remain able to play sports and do everyday activities until they reach adulthood.)

- During the first year of life inguinal and umbilical hernias are common.

- Less severe symptoms include:

- People with aspartylglucosaminuria may have lower than average height, because they tend to go through puberty earlier.

- Epilepsy may develop in adulthood.

- Finnish studies have shown that life expectancy is shorter than average.

The initial affected individual described in 1986 had a complex phenotype, and was later found to have both beta-mannosidosis and Sanfilippo syndrome. People have been described with a wide spectrum of clinical presentations from infants and children with intellectual disability to adults who present with isolated skin findings (angiokeratomas). Most cases are identified in the first year of life with respiratory infections, hearing loss and intellectual disability. Because of its rarity, and non-specific clinical findings, beta-mannosidosis can go undiagnosed until adulthood, where it can present with intellectual disability and behavioral problems, including aggression.

The symptoms of CCD are variable, but usually involve hypotonia (decreased muscle tone) at birth, mild delay in child development (highly variable between cases), weakness of the facial muscles, and skeletal malformations such as scoliosis and hip dislocation.

Symptoms may be present at birth or may appear at any stage of life. There appears to be a growing number of people who do not become symptomatic until adulthood to middle age. While generally not progressive, again there appears to be a growing number of people who do experience a slow clinically significant progression of symptomatology. These cases may hypothetically be due to the large number of gene mutations of ryanodine receptor malfunction, and with continued research may in fact be found to be clinical variants.

People with visible marks generally feel fine (physically) and can act normally, but when it is mentioned, they may become withdrawn and self-conscious. Some children may have low self-esteem due to the condition.

CMTC is an uncommon, sporadic congenital vascular malformation characterized by a generalized or localized reticulated cutaneous vascular network.

Cutaneous lesions described in patients with CMTC include nevus flammeus, hemangioma, nevus anemicus, café-au-lait spots, melanocytic nevus, aplasia cutis and acral cyanosis.

It has a marbled bluish to deep-purple appearance. The dark skin lesions often show a palpable loss of dermal substance. The reticulated mottling frequently appears more prominent in a cold environment (physiologic cutis marmorata), but tends not to disappear with warming. Hence, the erythema may be worsened by cooling, physical activity, or crying.

CMTC frequently involves the extremities, with the lower extremities involved most commonly, followed by the upper extremities, and then the trunk and face. The lower extremities often show atrophy and seldom show hypertrophy resulting in limb circumference discrepancy.

When located on the trunk, the lesions of CMTC tend to show mosaic distribution in streaks with a sharp midline demarcation seen across the abdomen. The lesions are primarily localized, but can be segmental or generalized, often unilateral in appearance. Diffuse involvement of the skin is usually not observed.

Although its course is variable, the majority of lesions in mild cases fade by adolescence. Ulceration and secondary infection are complications in severe cases and can be fatal if present in the neonatal period.

Symptoms and signs include abdominal discomfort, polyuria, polydipsia, incidental discovery of hypertension, abdominal mass. The classic presentation for ARPKD is systemic hypertension with progression to end-stage renal disease (ESRD) by the age of 15. In a typical presentation, a small number of ARPKD sufferers live to adulthood with some kidney function; but with significant deterioration in liver function. This outcome is postulated to result from expression of the polycystic kidney and hepatic disease gene PKHD1, which is located on chromosome 6p. In severe cases, a fetus will present with oligohydramnios and as a result, may present with Potter sequence.

The precise symptoms of a primary immunodeficiency depend on the type of defect. Generally, the symptoms and signs that lead to the diagnosis of an immunodeficiency include recurrent or persistent infections or developmental delay as a result of infection. Particular organ problems (e.g. diseases involving the skin, heart, facial development and skeletal system) may be present in certain conditions. Others predispose to autoimmune disease, where the immune system attacks the body's own tissues, or tumours (sometimes specific forms of cancer, such as lymphoma). The nature of the infections, as well as the additional features, may provide clues as to the exact nature of the immune defect.

A minority of patients are diagnosed with thymoma prior to manifestation of the immunodeficient state. Spindle-cell histology is present in most cases.

Because patients with GS have deficient humoral and cellular immunity, they are susceptible to a wide range of infections. Most commonly these patients suffer from respiratory tract infections. Chronic diarrhea is often related to villous atrophy rather than infection (Kelesidis, 2010).

Often autoimmune disease is associated with GS - most commonly pure red cell aplasia and myasthenia gravis. While the patients may experience hypogammaglobulinemia, a large percentage will have autoantibodies present in their serum (Kelesidis, 2010). It is theorized that the presence of thymoma may inhibit the thymus’s normal role in production of self-tolerant T lymphocytes. These T-lymphocytes may then attack the B cell precursors in the marrow, preventing maturation and ultimately resulting in hypogammaglobulinemia (Arnold, 2015).

Cutis marmorata telangiectatica congenita or CMTC is a rare congenital vascular disorder that usually manifests in affecting the blood vessels of the skin. The condition was first recognised and described in 1922 by Cato van Lohuizen, a Dutch pediatrician whose name was later adopted in the other common name used to describe the condition - Van Lohuizen Syndrome. CMTC is also used synonymously with congenital generalized phlebectasia, nevus vascularis reticularis, congenital phlebectasia, livedo telangiectatica, congenital livedo reticularis and Van Lohuizen syndrome.

It should not be confused with the more general term "cutis marmorata", which refers to livedo reticularis caused by cold.

The skin lesions evolve through characteristic stages:

1. blistering (from birth to about four months of age),

2. a wart-like rash (for several months),

3. swirling macular hyperpigmentation (from about six months of age into adulthood), followed by

4. linear hypopigmentation.

Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails are observed. Some patients have retinal vascular abnormalities predisposing to retinal detachment in early childhood. Cognitive delays/mental retardation are occasionally seen.

Discolored skin is caused by excessive deposits of melanin (normal skin pigment).

Most newborns with IP will develop discolored skin within the first two weeks.

The pigmentation involves the trunk and extremities, is slate-grey, blue or brown, and is distributed in irregular marbled or wavy lines.

The discoloration sometimes fades with age.

Neurological problems can include: cerebral atrophy, the formation of small cavities in the central white matter of the brain, and the loss of neurons in the cerebellar cortex.

About 20% of children with IP will have slow motor development, muscle weakness in one or both sides of the body, mental retardation, and seizures.

They are also likely to have visual problems, which can include: crossed eyes, cataracts, and severe visual loss.

Dental problems are common, and include missing or peg-shaped teeth - patients with IP often keep milk teeth into adult life.

Breast anomalies can occur in 1% of patients; anomalies can include hypoplasia and supernumerary nipples.

Skeletal and structural anomalies can occur in approximately 14% of patients, including:

- Somatic asymmetry,

- Hemivertebrae,

- Scoliosis,

- Spina bifida,

- Syndactyly,

- Acheiria (congenital absence of the hands - note: other limbs may be affected),

- Ear anomalies,

- Extra ribs,

- Skull deformities,

- Primary pulmonary hypertension,

- Cardiopulmonary failure

The onset of HLH occurs under the age of 1 year in ~70% of cases. Familial HLH should be suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. Each full sibling of a child with familial HLH has a 25% chance of developing the disease, a 50% chance of carrying the defective gene (which is very rarely associated with any risk of disease) and a 25% chance of not being affected and not carrying the gene defect.

Patients with HLH, especially when untreated, may need intensive therapy. Therefore, HLH should be included in the differential diagnosis of ICU (Intensive Care Unit) patients with cytopenia and hyperferritinemia.

HLH clinically manifests with fever, enlargement of the liver and spleen, enlarged lymph nodes, yellow discoloration of the skin and eyes, and a rash.

The hallmark of polymyositis is weakness and/or loss of muscle mass in the proximal musculature, as well as flexion of the neck and torso. These symptoms can be associated with marked pain in these areas as well. The hip extensors are often severely affected, leading to particular difficulty in ascending stairs and rising from a seated position. The skin involvement of dermatomyositis is absent in polymyositis. Dysphagia (difficulty swallowing) or other problems with esophageal motility occur in as many as 1/3 of patients. Low grade fever and peripheral adenopathy may be present. Foot drop in one or both feet can be a symptom of advanced polymyositis and inclusion body myositis. The systemic involvement of polymyositis includes interstitial lung disease (ILD) and cardiac disease, such as heart failure and conduction abnormalities.

Polymyositis tends to become evident in adulthood, presenting with bilateral proximal muscle weakness often noted in the upper legs due to early fatigue while walking. Sometimes the weakness presents itself as an inability to rise from a seated position without help or an inability to raise one's arms above one's head. The weakness is generally progressive, accompanied by lymphocytic inflammation (mainly cytotoxic T cells).

Central core disease (CCD), also known as central core myopathy, is an autosomal dominant congenital myopathy (inborn muscle disorder). It was first described by Shy and Magee in 1956. It is characterized by the appearance of the myofibril under the microscope.

There are no formal diagnostic criteria (Kelleher, 2003) and many informal definitions exist. Most commonly thymoma is present with mixed humoral and cellular immune deficiency. T and B cells are both depleted so patients suffer from both encapsulated organisms as well as opportunistic infections (Miyakis, 2005). Some have defined GS as a subset of common variable immunodeficiency (CVID). Unlike CVID, there are reduced B cells in the periphery in GS (Kelesidis, 2010).

More generally it can be defined as an adult-onset primary immunodeficiency associated with thymoma, hypogammaglobulinemia, diminished B and T cells, and inverted CD4/CD8+ ratio(Kelesidis, 2010).